Brooker2014 COHESINAS PDF

Chapter 11
The Roles of Cohesins in Mitosis, Meiosis,

and Human Health and Disease
Amanda S. Brooker and Karen M. Berkowitz
Abstract
Mitosis and meiosis are essential processes that occur during development. Throughout these processes,
cohesion is required to keep the sister chromatids together until their separation at anaphase. Cohesion is
created by multiprotein subunit complexes called cohesins. Although the subunits differ slightly in mitosis
and meiosis, the canonical cohesin complex is composed of four subunits that are quite diverse. The cohesin
complexes are also important for DNA repair, gene expression, development, and genome integrity. Here
we provide an overview of the roles of cohesins during these different events as well as their roles in human
health and disease, including the cohesinopathies. Although the exact roles and mechanisms of these pro-
teins are still being elucidated, this review serves as a guide for the current knowledge of cohesins.
Key words Cohesin, Mitosis, Meiosis, Sister chromatid cohesion, Cell cycle, Chromosome segrega-
tion, Aneuploidy, Human health, Cohesinopathies, Maternal age effect
1 Introduction
During the S phase of the cell cycle, DNA replication generates a

pair of sister chromatids with identical genetic content. The sister
chromatids must be physically connected through the G2 phase
and will only begin to separate during the transition from meta-
phase to anaphase during mitosis. The separation is completed in
anaphase owing to the loss of cohesion between the sister chroma-
tids. The end result is two daughter cells that are identical to each
other and to the parent cell. Separation of sister chromatids in
mitosis is the most important event during the cell cycle, and this
process must be monitored effectively.
Meiosis occurs strictly in germ cells and differs between males
and females. The key difference between meiosis and mitosis is that
meiotic cells undergo two cell divisions, meiosis I and meiosis II,
without an intervening S phase. During meiosis I, the chromatin
condenses as in mitosis and the sister chromatids are held together
through a process called cohesion. In prophase I, however, DNA
Eishi Noguchi and Mariana C. Gadaleta (eds.), Cell Cycle Control: Mechanisms and Protocols, Methods in Molecular Biology,
vol. 1170, DOI 10.1007/978-1-4939-0888-2_11, © Springer Science+Business Media New York 2014
229
230 Amanda S. Brooker and Karen M. Berkowitz
crossovers form between paired homologous chromosomes, called

bivalents. This involves chromosomal synapsis and formation of a
tripartite protein complex, the synaptonemal complex (SC), as well
as formation of chiasmata. Prophase I is divided into five distinct
substages: leptonema, zygonema, pachynema, diplonema, and dia-
kinesis. The bivalents, which are attached to microtubules through
their kinetochores and centromeres, align on the metaphase plate
during metaphase I. Unlike in mitosis, the sister chromatids remain
attached at their centromeres by cohesion, and only the homolo-
gous chromosomes segregate during anaphase I. The second mei-
otic division is exactly like the division in mitosis, with separation
of the sister chromatids. However, the end result is four haploid
spermatids or one haploid oocyte (and two or three polar bodies)
that are not identical to each other or to the parent cell.
Both mitosis and meiosis require cohesion to keep the sister
chromatids together until separation is imminent at anaphase.
Cohesion is established during DNA replication before both mito-
sis and meiosis by multiprotein subunit complexes called cohesins.
Although the subunits differ slightly in mitosis and meiosis, the
canonical cohesin complex is composed of four subunits. In mam-
mals these are the following: two structural maintenance of chro-
mosome (SMC) subunits (SMC1α or SMC1β and SMC3); one
stromalin, HEAT-repeat domain subunit (STAG1 or STAG2 or
STAG3 also called SA1 or SA2 or SA3, respectively); and one klei-
sin subunit protein (RAD21 or REC8 or RAD21L) (Fig. 1).
Because these subunits are quite diverse, a wide variety of cohesin
complexes with different subunit compositions exists in mitotic and
meiotic cells. These cohesin complexes are important for chromo-
some segregation, DNA repair, gene expression, development, and
genome integrity.
Although cohesins have been studied extensively, the exact
roles and mechanisms of these proteins are still being elucidated.
Recent interest focuses on the roles of cohesins in genome integ-
rity during mitosis and meiosis. The role sister chromatid cohesion
plays in replication fork maintenance is still unclear, but several
mechanisms have been proposed. Cohesins are also important in
double-strand break (DSB) repair and are implemented in cellular
responses to DNA damage. Exactly how these processes occur is
still unknown, but recent work is illuminating them. This review
highlights the importance of cohesins during mitosis and meiosis
by distinguishing different aspects of cohesin complexes and their
functions. We include the structure of cohesins, the tempo-spatial
association of cohesin subunits with chromosomes, recent mam-
malian studies involving targeted deletion of cohesin subunits, and
importance of cohesins in genome integrity. We also discuss the
roles and mechanisms of cohesins in human health and disease,
highlighting the cohesinopathies and the maternal age effect.
The Roles of Cohesins in Mitosis, Meiosis, and Human Health and Disease 231
SMC
SMCα/SMCβ
RAD/RADL/REC8 STAG/STAG/STAG
Fig. 1 Cohesin subunits form a ringlike structure. SMC1 and SMC3 form a
heterodimer, interacting through their hinge regions. The SMC1 and SMC3 head
domains, which contain ATPase motifs, interact with the C- and N-termini of the
REC8 or RAD21 or RAD21L kleisin subunit, effectively closing the ring. The STAG1
or STAG2 or STAG3 (also called SA1/SA2/SA3) subunit interacts with RAD21 or
RAD21L or REC8, contributing to maintenance of the ring structure. Mammalian
subunits are shown. Meiosis-specific subunits are depicted as underlined
2 Mitosis
During somatic cell division, several key events occur before a cell
can complete the cell cycle and divide into two identical cells. The
specific phases of the cell cycle and its checkpoints allow healthy
cells to divide and prevent abnormal cells from replicating. In
some instances, however, problems occur and the regulation of
the cell cycle is dysfunctional, leading to aberrant cell division.
The G1 checkpoint is designed to identify these errors, halt the
cell cycle, and to allow only functional cells to progress into S
phase. The G2 checkpoint ensures that the cell has replicated its
DNA correctly so that it can progress into mitosis and begin cell
division. During S phase of the cell cycle, the chromosomes
undergo DNA replication in order to produce identical sister
chromatids. The sister chromatids must be held together through-
out G2 phase and into mitosis by cohesin complexes, most of
which are conserved among eukaryotes. During prophase, the
loosely coiled chromatin begins to condense into distinct chromo-
somes while the spindle apparatus migrates to opposite poles of
the cell. In early metaphase the condensed chromosomes align on
the equatorial plate and then begin to separate in late metaphase
as the cell transitions into early anaphase. Cohesion between the
sister chromatids is maintained until this point, known as the
metaphase-to-anaphase transition. During early anaphase, the sis-
ter chromatids begin to separate to opposite poles via kinetochore

attachment to the spindle microtubules. Normally, sister kineto-
chores attach to microtubules with opposite orientations, known
as amphitelic attachment. Attachment of kinetochores to microtu-
bules with the same orientation is called syntelic. Failure to cor-
rect erroneous syntelic attachment during mitosis will lead to
improper segregation of sister chromatids and the gain or the loss
of chromosomes. Once sister chromatids have separated in late
anaphase, the final steps of telophase and cytokinesis yield two
daughter cells, which are identical to the parent cell.
2.1 What Is It is critical that cohesion between sister chromatids be maintained

Cohesion? until chromosome segregation occurs during both mitosis and
meiosis. Disruption of cohesion can lead to genome instability,
such as aneuploidy, defects in DNA repair, and chromosomal trans-
locations. Cohesion exists along the sister chromatid arms and at
centromeres. In late metaphase, the microtubules at the spindle
begin to contract to opposite poles of the cell, biorienting the sister
chromatids. Sister chromatid cohesion is an essential part of this
process, and it also provides a force that counteracts that exerted
by the microtubules [1]. Separation of sister chromatids occurs
only after chromosomes have bioriented on the metaphase plate,
triggering the dissolution of cohesion and subsequent migration to
the spindle poles [2] (Fig. 2). Cohesion between sister chromatids
results in a tight association that is not released until the meta-
phase-to-anaphase transition (Fig. 2). The linkage between the sis-
ter chromatids is especially crucial at centromeres because it ensures
correct microtubule attachment to the kinetochores.
2.2 Cohesins Create Sister chromatids are held together by multisubunit complexes
Cohesion Between called cohesins, which were first identified in the budding yeast,
Sister Chromatids Saccharomyces cerevisiae, and in Xenopus (Table 1). The cohesin
complex is evolutionarily conserved among eukaryotes and consists
of four main proteins. The core subunits of the cohesin complex in
budding yeast contain two subunits of the SMC family, Smc1 and
Smc3; a kleisin subunit protein Scc1/Mcd1; and a stromalin,
HEAT-repeat domain protein Scc3/Irr1 [3–6]. Homologues of
the cohesin subunits have been identified in a variety of eukaryotic
organisms from yeast to humans (Table 1). Higher eukaryotes have
three homologues of Scc3 termed SA1, SA2, and SA3, also known
as STAG1, STAG2, and STAG3 [7]. SA1/STAG1 and SA2/
STAG2 are present in mitosis, while SA3/STAG3 is specific to mei-
osis. Both SA1 and SA2 associate with the other cohesin subunits to
create a diverse group of cohesin complexes in vertebrates [7–9].
Two mammalian homologues of Smc1 are termed SMC1α, found
in both mitosis and meiosis, and SMC1β, which is specific to meio-
sis. Fission yeast Psc3 and Rec11 are also homologues of Scc3, but
Rec11 is required for cohesion during meiosis.
Scc/ Scc/ Scc/
Replisome
Eco1
S Phase
PCNA
Ctf18-
RLC
Metaphase
Separase
Anaphase
Fig. 2 Cohesion in yeast mitosis. Cohesin complexes require the Scc2/Scc4 pro-
tein complex in order to be loaded on chromosomes. Several proteins act
together to establish cohesion during DNA replication. These proteins include
Eco1 acetyltransferase, the CTF18–RLC complex, and the polymerase-associated
protein Ctf4. Tension at centromeres is generated by the bipolar attachment of
kinetochores to the mitotic spindle. Following biorientation of sister chromatids,
separase is activated to cleave the Scc1 subunit resulting in removal of cohesin
complexes, loss of cohesion, and separation of sister chromatids
A model of the cohesin complex has been frequently proposed

in which each proteinaceous ring entraps two sister chromatids [6,
10, 11]. The Smc1 and Smc3 molecules consist of long, rod-
shaped proteins that fold back on themselves at N and C terminal
domains to form long stretches of intramolecular and antiparallel
coiled coils [10, 12] (Fig. 1). A characteristic ATP-binding cassette
(ABC)-like ATPase is found at one end of the monomer and a half-
hinge domain at the other of each Smc1 and Smc3 molecule [12].
The ABC-like ATPase is a member of the protein superfamily that
utilizes the energy of ATP hydrolysis to carry out certain functions.
Table 1
Mitotic, meiotic, and regulatory protein homologues
Budding Fission
yeast yeast Mammals Xenopus C. elegans Drosophila
Cohesin Smc1 Psm1 SMC1α, SMC1β XSMC1 Him1 DCAP
subunits
Smc3 Psm3 SMC3 XSMC3 Smc3 Smc3
Scc1/Mcd1 Rad21 RAD21, RAD21L XRAD21, Coh2/Scc1 DRAD21
Rec8 REC8 XREC8 Rec8 DREC8
Scc3/Irr1 Psc3 SA1/STAG1, XSA1, Scc3 DSA1,
Rec11 SA2/STAG2, XSA2 DSA2/
SA3/STAG3 MNM
Loading Scc2 Mis4 NIPBL SCC2 Pqn-85 Nipped-B
Scc4 Ssl3 Mau2/Scc4 XSCC4 Mau2 Mau2
Establishment Ctf7/Eco1 Eso1 ESCO1, ESCO2 XECO1, Deco/San
XECO2
Maintenance Pds5 Pds5 PDS5A, PDS5B PDS5A, Pds5/Evl14 Pds5
PDS5B
Rad61 Wpl1 WAPL
Dissolution Pds1 Cut2 Securin Securin PIM
Esp1 Cut1 Separase Separin SSE/THR
Cdc5 Plo1 PLK1 PLX1 POLO
Sgo1 Sgo2 Shugoshin/ Shugoshin- MEI-S332
Sgo1 SGOL1 SGOL2 like 1
(xSGO1)
Bold denotes meiosis-specific
One Smc1 and one Smc3 molecule join together through their
hinge domains to form a heterodimer [10] when ATP binds. This
complex is then joined together by the Scc1/Mcd1/Rad21 sub-
unit, effectively closing the ring [5, 6]. The Scc1 N-terminus binds
Smc3, while the C-terminus of Scc1 binds Smc1. Scc3/SA1/SA2
binds to the C-terminus of Scc1 and does not make direct contact
with Smc1 or Smc3. Together these cohesin proteins form a very
distinct ring structure that are distinguished from other associated
proteins.
Biorientation of sister chromatids is tightly regulated and
requires several proteins that work in concert to allow the
metaphase-to-anaphase transition to occur. Separase is a mamma-
lian cysteine protease; it is the homologue of Esp1 in budding
yeast and Cut1 in fission yeast. When the centromeres are under
tension in metaphase, the mitotic checkpoint prevents separase
activation through Mad2 and Aurora B (Ipl1 in budding yeast)
[1]. When activated, Mad2 and Aurora B inhibit APCCdc20, a ubiq-
uitin ligase for securin, which in turn inhibits separase [13, 14].
This tension is relaxed once all the pairs have aligned correctly on
the metaphase plate. Aurora B/Ipl1 plays a crucial role in promot-

ing biorientation of sister chromatids [1, 15, 16]. In the absence
of Ipl1, attachment of sister kinetochores is syntelic, leading both
sister chromatids to segregate to the same daughter cell [16].
Aurora B plays a similar role in humans by destabilizing defective
kinetochore attachments, but only when there is no tension on
the kinetochores.
Several studies utilizing cohesin mutants have helped to eluci-
date the role of cohesins in sister chromatid cohesion; the mutants
were all incapable of keeping sister chromatids together during
metaphase [3–5, 17, 18]. In eukaryotic cells lacking cohesin, sister
chromatids separate precociously, leading to inefficient biorientation
and errors in segregation [19–21]. Mutations in cohesins have also
been shown to result in an increased distance between sister centro-
meres [3, 4]. Cohesin function has been studied in higher eukary-
otes by employing different techniques including gene deletion in
Xenopus and chickens and RNA interference (RNAi) in Drosophila
and humans. Scc1-deficient cells in chickens show chromosome mis-
alignment at metaphase, resulting in mitotic arrest or delay with
aberrant disjunction at anaphase [21]. Sonoda et al. also observed a
significant increase in distance between sister chromatids in Scc1-
deficient cells, but not full separation. Cells with separated sisters
and aberrant anaphases were also observed in Drosophila cells
depleted of DRAD21 by RNAi [22]. This phenotype, however, was
not observed in cells depleted of DSA1, the Drosophila homologue
of Scc3. These cells had cohered sisters and were able to progress
through anaphase normally, despite a slight increase in distance
between the sisters. In order to release the cohesin complexes from
the DNA, RAD21 is cleaved by separase in mammals. When a defi-
ciency in a cleavable form of RAD21 was expressed in human cells,
no loss of centromeric cohesion was observed in prophase or pro-
metaphase [23]. Anaphase, however, occurred aberrantly because
the separation of chromosome arms was perturbed. This finding
indicates that separation of the chromosome arms is promoted by
RAD21 cleavage and that cohesion-independent forces maintain
cohesion at centromeres until anaphase.
Although the structure of the cohesin complex forms a tripar-
tite ring [6, 10], how the complex associates with the DNA is not
well understood. Different ring models have been described, but
two types are most common (Fig. 3). One ring model predicts that
both sister chromatids are entrapped within a single cohesin ring
[6, 24]. This model proposes that the connection between the sisters
is topological rather than biochemical. The model would explain
why cohesin does not bind strongly to DNA on its own [25] and
why cohesin is readily released once the Scc1 subunit is cleaved [2].
Another type of ring model, the “handcuff” model, suggests that
each of the two cohesin rings entraps one sister chromatid, by
either binding a single Scc3 subunit or topological interconnection
a b
Ring Model Handcuff Model
Fig. 3 Models of cohesin rings. (a) One ring model predicts that both sister
chromatids are entrapped within a single cohesin ring. (b) Another type of ring
model, the “handcuff” model, proposes that each of the two cohesin rings
entraps one sister chromatid, by either binding a single Scc3 subunit or topologi-
cal interconnection between rings
between rings [26] (Fig. 3). The exact method by which the cohesin
complex associates with DNA has yet to be elucidated, but a few
models have been proposed.
2.3 The Association Sister chromatids are tightly associated through cohesion, which
and Dissociation prevents the separation of sisters before the metaphase-to-anaphase
of Cohesins transition (Fig. 2). As early as S phase of the cell cycle, cohesion
components are present in eukaryotes. For example, Scc1 in bud-
ding yeast associates with chromosomes during S phase and remains
tightly associated until the metaphase-to-anaphase transition [4]
(Fig. 2). When Scc1 expression is induced experimentally during
G2, it is ineffective at promoting cohesion because it is needed at the
time of DNA replication to establish sister chromatid cohesion [27].
Cohesion is also needed throughout G2 to facilitate the repair of
DSBs by homologous recombination between sister chromatids
[28]. Cohesins are recruited to DSBs in G2 and are implicated in
holding the sister chromatid with a DSB near its undamaged sister
template. Preventing cohesins from localizing to the DSBs actually
abolishes DNA repair [29]. The loading of cohesins is extremely
important from S phase through mitosis, but the dissociation signals
the beginning of segregation between the sister chromatids.
In budding yeast, the cohesin dissociation and destruction
process begins with proteolytic cleavage of the Scc1 subunit at spe-
cific residues by Esp1, a separin and protease [2, 30, 31] (Fig. 2).
This triggers the dissociation of cohesins from chromosomes that
is essential for the segregation of the sister chromatids to opposite
poles of the cell in anaphase [2]. This important step is disrupted in
Scc1 mutants as demonstrated by the premature separation of sister
chromatids [4]. Sister chromatids in yeast that express a non-cleavable
form of Scc1 resistant to Esp1 are unable to separate [2]. Conversely,

artificially targeting a different protease to Scc1 can still result in
premature separation of sister chromatids [30]. In fission yeast
only a small amount of the Scc1 homologue, Rad21, is cleaved at
the metaphase-to-anaphase transition to promote sister chromatid
separation [32]. A bulk of Rad21 associated with the chromosomes
remains during anaphase and may be necessary for the establish-
ment of cohesion at the next S phase. In lower eukaryotes the dis-
sociation process occurs in one step, but higher eukaryotes require
additional steps.
In vertebrate cells, cohesin dissociation is regulated by two
distinct pathways. A bulk of cohesins is removed from sister chro-
matid arms during prophase by a separase- and cleavage-indepen-
dent pathway [9, 33, 34] through phosphorylation by polo-like
kinases (PLK) and Aurora B [35–38]. This occurs when chromo-
somes begin to condense and also when they biorient on the
mitotic spindle during prometaphase. Phosphorylation of SA2/
STAG2 by Plk1 and Aurora B is essential for cohesion dissociation
during these stages, but it is not required in the next stage of
removal [39]. Hauf et al. have also shown that although RAD21
phosphorylation is not essential for cohesin dissociation in early
mitosis, it enhances the ability of separase to be cleaved during the
metaphase-to-anaphase transition. The cohesins remain at the
centromeres and are responsible for holding the sisters together
while they biorient during prometaphase. They are removed,
however, at the metaphase-to-anaphase transition when all the
chromosomes have correctly bioriented and the spindle assembly
checkpoint has been fulfilled. This occurs through an anaphase-
promoting complex or cyclosome (APC/C)- and separin-
dependent pathway by cleavage of RAD21 [34]. In human cells,
RAD21 is cleaved by separase, a step required to progress into
anaphase [40]. Separase is also required for cleavage of the remain-
ing cohesin complexes at sister chromatid arms during metaphase
in human cells [41].
Until the metaphase-to-anaphase transition, separase is kept
inactive by an inhibitory chaperone called securin [42], also known
as Pds1 in budding yeast [31, 43] and Cut2 in fission yeast [44].
Securin is controlled by the ubiquitin protein ligase APC/C. It is
destroyed via ubiquitination by the APC/C only after all the chro-
matid pairs have aligned correctly on the mitotic spindle, allowing
separase to become active. Once separase is activated in vertebrate
cells by the APC/C, it undergoes autocleavage, similar to that of
caspases. Separase cleaves RAD21 and the cohesin ring opens,
allowing the release of cohesion and separation of sister chroma-
tids. Sister chromatids do not separate in the presence of non-
cleavable Scc1, which suggests that separase may be the only mode
of cohesin removal from the sister chromatid arms.
2.4 Accessory Proteins that are essential for sister chromatid cohesion but not
Cohesion Factor structural components of the cohesin complex are known as acces-
Components sory or cofactor proteins (Table 1). Scc2 and Scc4 function together
in a complex to load cohesins onto chromosomes; they are con-
served among budding yeast and humans and are required for initial
cohesin binding to chromosomes [45, 46]. Cohesin is initially
loaded onto the Scc2–Scc4 complex at centromeres and at cohesion-
associated regions along sister chromatid arms (Fig. 2). Scc2 is con-
served in most eukaryotes; the fission yeast homologue is Mis4, and
the Drosophila homologue is Nipped-B, while the Scc4 homologue
in fission yeast is Ssl3. Metazoan Scc2 contains a heterochromatin
protein 1 (HP1)-binding domain that has been shown to interact
with HP1α, raising the possibility that Scc2 is directly involved in the
establishment and maintenance of heterochromatic domains [47].
Depletion of Scc4 results in severe premature sister chromatid sepa-
ration, suggesting that Scc4 is critical for chromosome cohesion in
actively dividing metazoan cells [46, 48]. Both Scc2 and Scc4 are
essential for cohesin loading onto chromosomes during S phase.
Pds5 [49, 50], WAPL [51], sororin [52], and haspin [53] are
involved in the regulation of cohesin complex association to and
dissociation from chromatin. These proteins physically associate
either directly or indirectly with the cohesin complex and they are
involved in cohesion maintenance. In humans, PDS5 interacts
with SA1/STAG1- and SA2/STAG2-containing complexes [9],
and in Caenorhabditis elegans PDS5 also has an important role in
sister chromatid cohesion during mitosis and meiosis [54]. Two
vertebrate PDS5 proteins have been characterized, PDS5A and
PDS5B, and depletion of these proteins from Xenopus extracts
results in partial defects in sister chromatid cohesion, but not in
mammals [55, 56]. Human WAPL regulates the resolution of sis-
ter chromatid cohesion and promotes cohesin complex dissocia-
tion during and after anaphase by direct interaction with the
RAD21 and SA/STAG subunits [51, 57]. WAPL has also been
found on axial and lateral elements (AE/LE) in some prophase I
stages in mouse spermatocytes and oocytes, colocalizing with
SYCP2 [58, 59]. Sororin was first identified in vertebrates during
a screen for substrates of the APC/C, but no homologues have
been characterized in other organisms [52]. Sororin is ubiquiti-
nated and degraded after cohesion is dissolved between sister chro-
matids. Recently, however, sororin has been shown to be necessary
for maintaining sister chromatid cohesion in mitotic cells as well as
for the stable binding of cohesin to chromatin and efficient repair
of DSBs in G2 [52, 60]. Haspin is a histone H3 threonine-3 kinase
that colocalizes with the cohesin complex at inner centromeres
during vertebrate mitosis. Depletion of haspin in human cells
results in premature separation of sister chromatids, suggesting a
role in the maintenance of centromeric cohesion prior to anaphase
[53]. Thus, PDS5, WAPL, sororin, and haspin are all important
mediators of cohesin complex function during mitosis.
2.5 Role of Cohesins Mutations and deletions in replication machinery components

in Genome Integrity result in defects in sister chromatid cohesion, suggesting a func-
tional relationship between processes that involve DNA replication
and cohesion establishment. This requires not only the cohesin
complex but also a number of accessory protein factors. Initial
studies in budding yeast demonstrated that the Eco1/Ctf7 acetyl-
transferase is required during S phase for cohesion establishment
[5, 61, 62] (Fig. 2). Eco1/Ctf7 mutations are synthetically lethal
with proliferating cell nuclear antigen (PCNA) mutations. The syn-
thetically lethal phenotype can be rescued, however, by overexpress-
ing PCNA. Recent work has shown that Eco1/Ctf7 is also necessary
to establish sister chromatid cohesion in G2/M in response to DSBs
[63]. The acetyltransferase domain of Eco1/Ctf7 and its activity are
required to generate cohesion during G2/M, as well as during S
phase. Thus, cohesion can be generated outside of S phase.
Homologues in fission yeast, Drosophila, and humans have been
termed Eso1, deco, and Esco2, respectively (Table 1).
Another group of proteins involved in establishing cohesion in
budding yeast are components of the replication machinery.
Investigators have suggested that stabilization of stalled replication
forks may be essential for proper establishment of cohesion. Ctf18
is a protein subunit of the alternative replication factor C-like com-
plex (Ctf18-RLC), a seven-subunit complex (Ctf18–Ctf8–Dcc1–
Rfc2–Rfc3–Rfc4–Rfc5). Ctf18–RLC establishes sister chromatid
cohesion and has been shown to load and unload PCNA onto and
off of DNA [64–67]. Eco1/Ctf7, Ctf4, and Ctf18-RLC all act in
close proximity to the replication fork and are essential for cohe-
sion [68] (Fig. 2). Ctf4 associates with replication origins and with
DNA polymerase α and moves with the replication machinery
along chromosomes [66, 67]. Recent work has suggested that
Eco1/Ctf7 and Ctf18-RLC colocalize with replication forks, but it
is not known whether they move with the replication machinery.
In their absence, however, sister chromatid cohesion is compro-
mised. Stabilization or “protection” of stalled replication forks and
proper sister chromatid cohesion involves proteins Swi1–Swi3,
Ctf18-RLC, and Chl1 in fission yeast [69]. The Swi1–Swi3 com-
plex plays an important role in efficient activation of Cds1, a repli-
cation checkpoint kinase. The complex moves with replication
forks and is required to prevent accumulation of single-stranded
DNA structures near the replication fork [70]. Homologues of
Swi–Swi3 exist as the Timeless–Tipin complex in humans and the
Tof1–Csm3 complex in budding yeast. The DNA helicase activity
of Chl1 is evolutionarily conserved and appears to be involved in
sister chromatid cohesion. In fission yeast, Chl1 has been shown to
stabilize replication forks and to promote proper establishment of
sister cohesion [69], and in budding yeast Chl1 associates with
Eco1/Ctf7 for critical involvement in chromatid cohesion [71].
ChlR1, the homologue of Chl1 in mammals, binds cohesin and is
required for normal sister chromatid cohesion [72]. Depletion of
ChlR1 results in abnormal sister cohesion and a delay at prometa-

phase. These proteins are critical for cohesion between sister chro-
matids, but their functions have not been fully elucidated.
In this same context, Ctf18-RLC has been suggested to con-
trol the speed, spacing, and restart activity of replication forks in
human cells and is also required for robust acetylation of SMC3
and sister chromatid cohesion [73]. Terret et al. also found that
cohesin acetylation itself is a “central determinant of fork proces-
sivity,” because slow-moving replication forks were found in
human cells expressing a form of non-acetylatable SMC3 and in
cells lacking the Eco1-related acetyltransferases, ESCO1 or
ESCO2. The defect was a consequence of the strong interaction
between cohesin and the regulatory cofactors WAPL and PDS5A
because removal of either cofactor allowed forks to progress rap-
idly without ESCO1, ESCO2, or Ctf18-RLC. Although only
demonstrated in human cells, these findings suggest a possible
new mechanism for clamp loader-dependent fork progression,
resulting from the posttranslational modification and structural
remodeling of the cohesin ring [73].
Several mechanisms have been proposed for the role of replica-
tion fork maintenance in sister chromatid cohesion. One model
proposes that cohesin bound to chromosomes before arrival of the
replication fork is sufficient to establish sister chromatid cohesion
[68]. Therefore, it is thought that the replication machinery slides
through the cohesin rings. However, Lengronne et al. have also
proposed that the cohesin complex may transiently dissociate upon
fork passage through the rings. Fork components, such as Ctf18-
RLC and/or Swi1–Swi3, may tether cohesin-related proteins to
DNA when forks pass through the cohesin ring [69]. CHTF18,
the gene product of the human Ctf18 homologue, has been shown
to interact with several cohesin proteins, supporting this idea [64];
recent work also supports a possible interaction of CHTF18 with
cohesins during mammalian meiosis [74]. Another model suggests
that the cohesin ring may be an obstacle for replication fork pro-
gression and causes stalling of the fork [69]. This would require
stabilizing proteins, such as Swi1–Swi3 and Ctf18-RLC, at cohesin
sites. A third model proposes that Ctf18-dependent unloading of
PCNA might loosen the replication fork structure in order for the
forks to pass through the cohesin ring without its dissociation
[65]. A very recent model proposes that sister chromatid cohesion
is established simultaneously with cohesin loading behind the rep-
lication fork in close proximity to processing of the lagging strand
[75]. Although several models have been proposed, the exact
mechanism for replication fork maintenance in sister chromatid
cohesion remains unknown.
Cohesins are also involved in cellular responses to DNA dam-
age [76]. Mammalian cohesins are recruited to DSBs; they take
part in the ataxia telangiectasia mutant (ATM) DNA damage signal
transduction pathway and are important for survival after irradia-

tion [76]. Two different populations of cohesins contribute to the
repair process: cohesins engaged in holding sisters together at the
time of the break and cohesins subsequently recruited to chroma-
tin surrounding the break itself [29, 77]. After induction of DSBs,
cohesins are recruited to these sites via the DNA damage response
pathway. Because recombination between sister chromatids is gen-
erally more efficient than between homologous chromosomes,
cohesin might inhibit recombination between the homologues.
Suppressing recombination between homologues is important in
preventing chromosome instability and rearrangements such as
nonallelic recombination and/or loss of heterozygosity. In bud-
ding yeast the cohesin complex encoded by MCD1 genes plays a
dual role in protecting chromosome and genome integrity [78].
Even a small reduction in the levels of cohesin subunits decreases
DSB repair and significantly increases damage-induced recombina-
tion between homologous chromosomes. Thus, cohesin levels
appear to be a limiting factor in controlling genome integrity [78].
Phosphorylation of cohesin SMC subunits has also been found
to be implemented in the cellular response to DNA damage. In
response to ionizing radiation, the phosphorylation of S957 and
S966 of human SMC1 by ATM kinase is required for the activation
of the S-phase checkpoint [79]. Mutant cells defective in SMC1
phosphorylation still exhibited formation of DNA damage foci
after exposure to ionizing radiation [80]. However, these cells
show decreased survival, chromosomal anomalies, and a defective
S-phase checkpoint after DNA damage. Investigators have also
reported that SMC3 is phosphorylated at two specific serine resi-
dues as well as by two different kinases [81]. Human SMC3 S1083
phosphorylation is inducible and ATM dependent by ionizing
radiation, while S1067 is constitutively phosphorylated by CK2
kinase and not increased by ionizing radiation. Phosphorylation of
both of these sites, however, is required for the S-phase check-
point. The roles of cohesins in genome integrity are still being
elucidated, but it is well known that cohesins play a larger role dur-
ing mitosis than originally thought.
3 Meiosis
Although the process of meiosis is similar to mitosis, haploid gam-

etes are generated instead of diploid cells. Several distinct differ-
ences between the two processes have been established, and
cohesins play a vital role in many aspects of meiosis. Meiosis begins
in diploid germ cells following one round of DNA replication in
which maternal and paternal homologous chromosomes have
been duplicated, each chromosome consisting of two sister chro-
matids (4C DNA content). Ultimately, these duplicated pairs of
sister chromatids are separated into four different nuclei by two

rounds of cell division without any intervening DNA replication.
In mammals, male meiosis gives rise to four different haploid
gametes (spermatids) whereas female meiosis gives rise to ulti-
mately one haploid gamete (oocyte) and two or three polar bod-
ies. During the first meiotic division (meiosis I), pairs of maternal
and paternal homologous chromosomes ultimately segregate in
opposite directions. This reduces the chromosome number and
also ensures that each gamete will inherit a complete copy of the
genome. Pairs of sister chromatids then separate in the second
meiotic division (meiosis II) as in mitosis.
Meiosis I is unique in the manner of chromosome segrega-
tion and in the distinct processes that occur during prophase
I. Homologous recombination is an essential phenomenon during
meiosis because it physically joins the maternal and paternal homo-
logues before segregation and ultimately generates new combina-
tions of alleles and genetic variation. Homologous recombination
during meiosis I (also called meiotic recombination) results in the
exchange of DNA between maternal and paternal chromatids, and
the sites of DNA exchange are called crossovers. Crossovers are seen
cytologically as structures called chiasmata. Chiasmata and cohesion
along sister chromatid arms hold homologous chromosomes
together prior to their segregation in anaphase I. Attachment of
sister kinetochores to microtubules with the same polarity, called
syntelic attachment, is another feature that is unique to meiosis
I. This type of attachment of sister kinetochores is also known as
mono-orientation, and it differs from the biorientation of sister
kinetochores during mitosis. Because the chiasmata physically link
homologous chromosomes, tension is generated and a new form of
equilibrium is established during metaphase I. Chiasmata ensure
that the tension will be generated if both maternal centromeres
attach to microtubules with one orientation and both paternal cen-
tromeres attach to microtubules with the opposite orientation.
The spindle machinery senses this bipolar attachment-like tension
between homologous chromosomes and not sister chromatids in
metaphase I. Although tension on homologues of maternal and
paternal centromeres pulls them in opposite directions, they are pre-
vented from disjoining during prophase I by the presence of chias-
mata and cohesion between sister chromatids. Cells systematically
suppress amphitelic attachment and promote syntelic attachment of
the sister chromatids during the first meiotic division to prevent
aneuploidy. During the second meiotic division sister kinetochores
attach to microtubules in an amphitelic manner and the sisters are
segregated to opposite poles during the metaphase-to-anaphase
transition, as in mitosis. Only sister chromatid arm cohesion is
destroyed during anaphase I, leaving centromeric cohesion to per-
sist. This process, along with resolution of chiasmata, results in the
separation of homologues only and not sister chromatids during
Homologous
Pre-meiotic
Chromosomes
S Phase
Metaphase I
Separase
Anaphase I
Fig. 4 Cohesion in yeast meiosis I. Rec8 replaces Scc1 of the cohesin complex in
S phase. During prophase I homologous chromosomes pair and meiotic recom-
bination leads to DNA crossovers between non-sister chromatids. In order for
homologous chromosomes to segregate, kinetochores of sister chromatid pairs
must each be mono-oriented to opposite poles during metaphase I. Separase
cleavage of Rec8 during anaphase I, much like that during mitosis, resolves the
cohesion distal to crossovers to allow segregation of homologues. In order to
allow for the proper biorientation and segregation of sister chromatids during
meiosis II, cohesion proximal to centromeres is preserved
anaphase I. Centromeric cohesion in meiosis II is essential to ensure

the bipolar attachment of sister kinetochores as in mitosis.
Cohesion between sister chromatids is established during pre-
meiotic DNA replication and differs from its mitotic counterparts
(Fig. 4). Meiotic cohesins must participate in the recombination
process as well as persist at centromeres through the first division.
However, cohesion along sister chromatid arms must dissolve dur-
ing meiosis I to allow the homologues, joined by chiasmata, to
separate (Fig. 4). The cohesion along sister chromatid arms ensures
correct chromosome alignment during the first division, and
cohesion at the centromeres ensures proper segregation at the

second division [82, 83]. Once cohesion between sister chromatid
arms is released, the microtubules pull maternal and paternal cen-
tromere pairs to opposite poles of the cell. These different types of
cohesion are extremely important during meiosis because the
chromosomes must undergo two distinct rounds of segregation.
Cohesion at the centromeres ensures biorientation of chromatids
on the spindle and accurate segregation during meiosis II, as in
mitosis. The destruction of centromeric sister chromatid cohesion
triggers their disjunction and segregation to opposite poles of the
cell, yielding haploid cells. The two steps involved in cohesin
removal during meiosis are similar to the steps in prophase and
anaphase of mitosis.
Meiotic recombination has been most well characterized in
yeast. The process begins with generation of DNA DSBs by Spo11
endonuclease [84]. This occurs in early prophase I at multiple
locations along each of the four chromatids. The 5′ ends resulting
from Spo11 cleavage are resected in yeast by Rad50, Mre11, and
Com1/Sae2 to form single-stranded 3′ overhangs on each side of
the break [85–87]. First-end capture occurs by one 3′ overhang
invading the homologous non-sister chromatid [88]. The invading
3′ end becomes paired with the complementary strand from the
other chromatid, creating a template for repair. The displaced
strand will then pair with the second 3′ overhang on the original
chromatid. The ends are ligated to the newly synthesized DNA,
creating a joint molecule. At this point, the non-sister chromatids
(one maternal and one paternal) will have recombined homologues
and crossing over will be complete, creating a double Holliday
junction (DHJ). The final step in the recombination process is the
resolution of DHJs by cleaving of a pair of chromosome strands at
each end and their reciprocal ligation. The cleavage can be either
horizontal or vertical, but crossover occurs only when one junction
is resolved horizontally and the other vertically. Most organisms
create several of these exchanges per chromosome, but only one
chiasma is needed to hold a pair of homologous chromosomes
together.
3.1 Unique Meiotic The cohesin complex in germ cells differs from somatic cells, and
Cohesin distinct meiosis-specific subunits have been characterized in various
Characteristics organisms. In both fission and budding yeast, Rad21 is involved in
mitosis and Rec8 is the meiotic paralogue of Scc1 [82, 89, 90].
Fission yeast has two Scc3 homologues, Rec11 and Psc3 (Table 1).
Rec11 is meiosis-specific and forms a complex with Rec8, mainly
along the chromosome arm regions, and the complex is critical for
recombination [91]. Psc3, however, is expressed in mitosis and mei-
osis and associates with Rec8 mainly at the centromeres. Although
inactivation of Rec11 impairs sister chromatid cohesion specifically
along the arm and reduces the rate of recombination, Psc3 is
SMC SMCα SMC SMCα
RAD SA/SA RADL STAG
SMC SMCβ SMC SMCβ SMC SMCβ
RAD STAG RADL STAG REC STAG
Fig. 5 Putative subunit compositions of some of the cohesin complexes in mammals. Differences in spatiotem-
poral distribution occur throughout the meiotic divisions
dispensable for these functions but it is required for centromeric

cohesion persisting throughout meiosis I. In mammals, the meiotic
paralogues of SMC1, SCC1/RAD21, and SA/STAG1/2 are
SMC1β, REC8, and SA3/STAG3, respectively [92–96] (Table 1).
Although these three subunits are strictly expressed in germ cells,
SMC1α, RAD21, and SA2/STAG2 are also implemented in meiotic
chromosome dynamics [97]. Recently, a third kleisin subunit in
mammals, named RAD21L, has been identified in meiotic cells and
localizes along the AE/LEs of the SC throughout meiosis I
[98–101]. This subunit may be involved in synapsis initiation and
crossover formation between homologous chromosomes. RAD21L
has also been shown to be a functionally relevant meiotic kleisin
subunit that is essential for male fertility and maintenance of fertility
during natural aging in females [99]. Evidence for participation of
different cohesin complexes during mammalian meiosis suggests a
variety of putative cohesin complexes formed by combinations of
cohesin subunits (Fig. 5). Several distinct complexes are thought to
exist, showing differences in spatiotemporal distribution throughout
the meiotic divisions.
3.2 Cohesins In yeast Chl1, Ctf4, and Ctf18-RLC are necessary for sister chro-
in Genome Integrity matid cohesion in both mitosis and meiosis, and they are essential
During Meiosis for chromosome segregation during meiosis. In fact, they contrib-
ute significantly to the establishment of cohesion in the region of
centromeres. Deletion of CTF18, or CHL1, or CTF4 in budding
yeast leads to severe defects in chromosome segregation, aneu-
ploidy in the spores, and meiosis II nondisjunction at a high fre-
quency [102]. In yeast, frequent errors in meiosis II, rather than

homologue nondisjunction in meiosis I, predominantly contribute
to the mis-segregation phenotype in meiotic mutant cells.
Cohesin is particularly important in meiotic cells to hold biva-
lents together during homologous recombination and DSB repair.
Whether cohesin is actively recruited to sites of DSBs during meio-
sis, as it is in mitotic cells, is not well known. A conserved DNA
damage checkpoint, known as the pachytene checkpoint, also moni-
tors the efficient repair of meiotic DSBs and induces apoptosis when
DSBs are not repaired in a timely fashion. The involvement of cohe-
sin in repair of meiotic DSBs and activation of the pachytene check-
point have been demonstrated in the C. elegans germline [103].
Loading of cohesin onto chromatin during S phase, and also in
response to DSBs in post-replicative cells, depends on a conserved
complex composed of Scc2 and Scc4 proteins. Meiotic cohesin is
loaded by Scc2, and in the absence of meiotic cohesin, recombina-
tion intermediates accumulate extensively but fail to trigger the
apoptotic response of the pachytene checkpoint [103]. Meiotic
cohesion is required for early DSB processing and for efficient
recruitment of DNA damage sensors [103]. This suggests that cohe-
sin is involved in early events of the meiotic DNA damage response.
3.3 Specific Events Prophase I is prolonged in mammalian meiosis, and it is divided

in Meiosis I and II into substages according to chromatin changes based on cytological
studies. The most important event during prophase I is formation
of the SC, which forms between homologous chromosomes. This
structure supports meiotic recombination, and it represents an
essential difference between mitosis and meiosis. Meiosis-specific
cohesin complexes are believed to form a scaffold to which compo-
nents of the SC can attach.
During leptonema of prophase I, the AE form along each
chromosome. SYCP2 and SYCP3 create a bipartite polymer along
the bivalent axes and are the main structural protein components
of the AE/LE [104–107]. Then in zygonema, homologues begin
to pair and central elements (CE) are deposited between the AE
(now called LE). Zip1 in yeast and SYCP1 in mammals, known as
transverse filaments, form the center of the SC or the central ele-
ments. In pachynema, homologues synapse along their length, the
SC fully forms, and DNA recombination takes place. This close
association between maternal and paternal axes along the entire
length of the bivalent is called synapsis, and it is achieved by the
SC. The onset of diplonema is characterized by the disassembly of
the SC and homologue desynapsis. The final stage of prophase I is
diakinesis, which quickly progresses into metaphase I. Homologues
remain connected at chiasmata, which can now be seen cytologi-
cally at this stage, and cohesion between sister chromatids prevents
premature segregation. Immunocytological studies have helped
characterize the spatiotemporal localization of cohesins during
meiosis.
3.3.1 Leptonema During prophase I in spermatocytes, cohesin subunits are observed

at different stages and in different quantities. SMC1β can be
observed along the asynapsed AE, and STAG3 is found along the
AE during leptonema [95, 96]. REC8 is localized along asynapsed,
synapsed, and desynapsed AE/LE throughout prophase I [92].
RAD21, like REC8, also appears at the AE/LE during all stages of
prophase I [108, 109]. RAD21L is expressed from premeiotic S
phase and localizes along the AE in leptonema, with some conflict-
ing reports as to whether it persists to mid-pachynema or diplo-
nema and into metaphase I [98–101].
3.3.2 Zygonema In the zygotene stage of prophase I, SMC1β is found along the
asynapsed AE and also the synapsed LE [96]. SMC1α and SMC3
are observed in a distinct punctate pattern along the synapsed LE
in late zygonema and are found to interact with SYCP2 and SYCP3,
structural protein components of the SC [110]. STAG3 is observed
along the AE/LE as in leptonema [95]. RAD21L localizes along
the AE/LE in zygonema in a punctate or a continuous linear
pattern depending on the report [98–101].
3.3.3 Pachynema During pachynema, SMC1α and SMC3 are still seen immunocyto-
logically in a distinct punctate pattern along the synapsed LE and
interact with SYCP2 and SYCP3 [96, 110]. SMC1β and STAG3
are also found along the synapsed LE. Although RAD21L is dis-
tributed along the SC through at least mid-pachynema, reports of
its localization vary. Some groups have reported that RAD21L is
evenly distributed along the AE/LE, while other groups have
reported that it is discontinuous [98–101]. In addition, two groups
have reported that RAD21L localizes in a mutually exclusive pat-
tern with REC8, perhaps suggesting inherent loading sites for
these cohesins [100, 101].
3.3.4 Diplonema/ SMC1α is lost from the desynapsed LE during diplonema and it is
Diakinesis not detected on bivalents in diakinesis or metaphase I. SMC3, how-
ever, persists at the desynapsed LE but is progressively lost and accu-
mulates at centromeres during diakinesis. SMC1β is found along the
desynapsed LE, most of it dissociating in late diplonema, and accu-
mulating at the centromeres during diakinesis. STAG3 is still visible
along the LE but is observed as patches along the contact surface
between sister chromatids, called the “interchromatid domain,”
during diakinesis [95, 111]. This subunit is maintained at the chro-
mosome arms and centromeres until metaphase I [95]. During late
diplonema, RAD21 appears along desynapsed LE but also accumu-
lates in areas where it is colocalized with SYCP3. By late diplonema
to diakinesis, RAD21 is partially released from the LE [108]. REC8
has been found at the interchromatid domain along chromosome
arms and centromeres during diakinesis and metaphase I bivalents
[92, 110]. RAD21L disappears by mid-pachynema or diplonema as
it accumulates at centromeres [98–101].
Based on the studies mentioned here, several different cohesin

complexes are present during mammalian prophase I (Fig. 5). The
complex, SMC1α/SMC3/RAD21/SA1 or SA2, is present during
premeiotic S phase. SMC1α/SMC3/RAD21L/STAG3 and
SMC1β/SMC3/RAD21L/STAG3 are present along the AE/LE
from premeiotic S phase through diplonema. The canonical meiotic
complex, SMC1β/SMC3/REC8/STAG3, and the SMC1β/SMC3/
RAD21/STAG3 complex are likely present throughout prophase I.
These complexes ensure that at the end of prophase I homologous
chromosomes remain connected at chiasmata despite dissolution of
the SC.
3.3.5 Metaphase I In metaphase I mammalian spermatocytes, STAG3 is seen as dis-

continuous bright patches lining the interchromatid domain along
sister chromatid arms, but not at chiasmata [95]. STAG3 is also
present at the centromere domain just below the closely associated
sister kinetochores. The same pattern of labeling has also been
reported for REC8 [92, 110]. SMC3 was initially reported to be
concentrated at centromeres and absent from chromosome arms
[96, 112]. However, recent work has suggested that SMC3, like
STAG3 and REC8, is distributed along the interchromatid and
centromere domains of metaphase I bivalents [113]. The distribu-
tion of RAD21 is distinctive; it accumulates at the inner centro-
mere domain in a “double cornet-like” configuration with SYCP2
and SYCP3 and is also seen as small patches at the interchromatid
domain [108]. SMC1β also localizes with SYCP2 and SYCP3 to
mainly the centromeres of metaphase I spermatocytes, but the
exact configuration at the inner centromere domain has not been
studied [114]. Studies suggest that RAD21L remains in residual
amounts, partly colocalized with SYCP3 at or near centromeres,
although reports are conflicting [98–101].
3.3.6 Anaphase The exact localization pattern of cohesin subunits from anaphase I
I to Metaphase II to metaphase II is not known. REC8, STAG3, RAD21, SMC3,
and SMC1β persist at centromeres during anaphase I, although
their patterns differ [92, 95, 108, 109, 112]. The dynamics of
these subunits are unknown during telophase I and interkinesis,
but some information is known about a few of the subunits.
RAD21 changes its distribution to a bar-like pattern in between
sister kinetochores at telophase I centromeres [108]. These bars
are also seen during interkinesis at “heterochromatic chromocen-
ters,” which represent closely associated centromeres [108, 113].
This pattern disappears at prophase II. STAG3 and REC8 have
also been reported to disappear from centromeres during telophase
I and are no longer seen in interkinesis nuclei [95, 113, 115].
3.3.7 Metaphase II Reports regarding the appearance and distribution of cohesin sub-
units at centromeres in metaphase II are conflicting. Original
studies in rodent surface-spread spermatocytes indicated that

RAD21, SMC1β, and SYCP3 appeared as rod-shaped aggregates
between sister centromeres [96, 109]. However, RAD21 and
SYCP3 were not visualized at centromeres in squashed spermato-
cytes [108, 115]. The conflicting results obtained are attributed to
differences in the techniques used as well as possible differences in
the ability to detect small amounts of the cohesins [108, 113, 115].
3.3.8 Female Meiosis Although features of meiosis are similar in male and female mam-
mals, important gender-specific differences exist in the onset, tim-
ing, duration, and outcome of meiotic processes. Female germ
cells enter meiosis as oocytes during fetal development and arrest
at the end of the diplotene stage of prophase I, known as dictyate.
Dictyate arrest lasts from the late stages of fetal development until
resumption of meiosis just prior to ovulation. Information regard-
ing chromosome cohesion during this extended time frame and
whether cohesin complexes established during fetal life are present
decades later is not known. Localization patterns of several meiotic
cohesins have been compared to SYCP3 during the formation and
dissolution of the SC in fetal oocytes during human and murine
prophase I [116]. Results from this study suggested that STAG3,
REC8, SMC1β, and SMC3 associate with chromatin to form a
“cohesin axis” prior to AE formation during female meiosis in
mammals [116]. In human fetal oocytes STAG3 and REC8 are
scattered throughout preleptotene nuclei but become more orga-
nized in leptonema and partially colocalize with SYCP3. By zygo-
nema, however, REC8 and STAG3 colocalize with SYCP3 and
persist into early diplonema. In mouse oocytes expression of
STAG3, SMC3, and SMC1β first appears as fibers in leptonema
prior to AE formation, similar to the timing of cohesin axis forma-
tion in human oocytes. The cohesin fibers become more promi-
nent in zygonema with AE formation and then colocalize with
SYCP3 in pachynema. During dictyate arrest in mouse oocytes
there is gradual loss of both SYCP3 and the cohesin axis [116].
A recent study analyzed the distribution of SMC3, REC8,
SMC1β, STAG3, and SYCP3 in human oocytes throughout meiosis
[117]. As meiosis progresses into leptonema in oocytes, the cohesins
appear as thin threads and their staining completely overlaps with
SYCP3 and remains colocalized through diplonema. Unlike mouse
oocytes, cohesins do not appear to be lost during dictyate arrest in
human oocytes. REC8, STAG3, and SMC3 appear as short fila-
ments with a diffuse pattern of distribution in the nucleoplasm and
cytoplasm [117]. SMC1β, however, appears intensely all over the
oocyte, including the nucleus and cytoplasm. In fully grown germi-
nal vesicle oocytes STAG3 appears as cohesin threads all over the
chromatin, including intense staining at the nucleolus. In metaphase
I oocytes, cohesins are seen as bright patches along the interchroma-
tid domain and the centromeric area of all bivalents. From early
anaphase I, cohesins are no longer seen at the arms of sister chroma-

tids and are confined to the centromeric area. At metaphase II,
REC8, STAG3, SMC1β, and SMC3 are observed in the space
between sister kinetochores, and SYCP3 appears as small dots par-
tially colocalizing with each sister kinetochore.
3.3.9 Synaptonemal One component of the CE unique to mammals is FK506-binding

Complex: Central Elements protein 6 (FKBP6), which belongs to the FKBP family of proteins
and Cohesin Function and is expressed in mouse male and female germ cells during pro-
phase I [118]. FKBP6 localizes to SYCP1 of synapsed chromo-
some cores and also coimmunoprecipitates with SYCP1, suggesting
a role in the assembly and maintenance of the SC [118, 119].
FKBP6 appears to interact with NEK1, a never-in-mitosis A
(NIMA)-related kinase 1 dual-specificity serine–threonine and
tyrosine kinase [119]. NEK1 is highly expressed in spermatogonial
cells and spermatocytes during prophase I in mice. SMC3 staining
decreases and becomes more diffuse in spermatocytes of wild-type
mice during diplonema. However, SMC3 persists in diplotene
Nek1-deficient spermatocytes, consistent with a role of NEK1 in
removal of the meiotic cohesin SMC3 from chromosome cores at
the end of prophase I [119]. Similar findings are observed in
Fkbp6-null spermatocytes, suggesting that the FKBP6–NEK1
pathway may be involved in cohesin removal at the end of pro-
phase I. However, normal accumulation of SC and DSB repair
proteins is seen in Nek1-deficient spermatocytes [119].
3.4 Loss of Cohesion Destruction of cohesion distal to chiasmata is mediated by the

Through Destruction same mechanism that triggers disjunction of chromatids in mitosis.
of Cohesins Rec8 is present along sister chromatid arms during metaphase I
but disappears from the arms at the onset of anaphase I in budding
yeast and mice [82, 83, 92]. In budding yeast resolution of chias-
mata and removal of Rec8 from sister chromatid arms depend on
cleavage by separase, just like Scc1 in mitosis [120]. However,
Rec8 remains in the area of centromeres until the onset of ana-
phase II in budding yeast [82], fission yeast [83], C. elegans [121],
and mouse spermatocytes [92]. These findings suggest that eukary-
otic organisms maintain sufficient cohesion around centromeres
during meiosis II by protecting Rec8 from separase cleavage dur-
ing meiosis I. Mutations in rec8 result in precocious separation of
sister chromatids during anaphase I. In fission yeast, Rad21 ectopi-
cally expressed at centromeres cannot rescue this defect, suggest-
ing that Rec8 is responsible for the persisting centromeric cohesion
until meiosis II and it cannot be replaced by Rad21 [89]. Protection
of centromeric Rec8 is lost after anaphase I, as indicated by the dis-
sociation of Rec8 from chromosomes with reactivation of separase
at the onset of anaphase II. If the protection were to dissolve prior
to inactivation of separase, premature disjunction of sister centro-
meres would occur. It is interesting, however, that exchange of
Scc1 for Rec8 during mitosis does not prevent cohesin cleavage at
the centromere, suggesting that other meiosis-specific factors are
involved [120]. In C. elegans, where separase is also required for
meiosis I, the phosphorylation of Rec8 by the Aurora B protein
Air2 might ensure that only Rec8 distal to chiasmata is cleaved at
the first division [122–124]. In budding and fission yeast, the
expression of a nondegradable form of Rec8 that carries mutations
at the separase target sites dominantly blocks the onset of anaphase
I. This phenotype is suppressed by the elimination of chiasmata,
suggesting that the separase-mediated cleavage of Rec8 triggers
homologue separation by resolving chiasmata on the arm regions
[120, 125]. An accumulation of securin, the inhibitory chaperone
of separase, has been observed not only in meiosis I but also in
meiosis II, indicating separase activation at both meiotic divisions
[120, 125]. The same observation has been made in C. elegans and
in mice, where the activation of securin is crucial for the progres-
sion of meiosis I [122, 126, 127].
Identification of a protein that protects centromeric cohesion
during prophase I has revealed why centromeric Rec8 is only
cleaved during meiosis II and not during meiosis I. In fission yeast
this protector of Rec8 centromeric cohesion is a gene product that
when coexpresssed with Rec8 causes toxicity during mitotic growth
[128]. The gene encodes a meiosis-specific protein named shu-
goshin (Sgo1), a homologue of the Drosophila protector Mei-S332
[129–131]. Shugoshin associates with protein phosphatase 2A
(PP2A) and forms a complex at centromeres, which blocks the
cohesin phosphorylation necessary for removal of cohesion and
also prevents premature loss of centromere cohesion [132, 133].
Fission yeast Sgo1 localizes exclusively at the site where Rec8 is
predicted to have a role in centromeric protection during meiosis I
[91]. Budding yeast shugoshin is also thought to have the same
effect on Rec8 during meiosis I [128, 130, 131]. Fission yeast and
mammals also possess paralogues of Sgo1 called Sgo2 and SGOL2,
respectively. Their proteins are ubiquitously expressed throughout
the mitotic and meiotic cell cycle in yeast, [128, 129] but only
SGOL2 is essential for meiosis in mammals [134]. However, both
SGOL1 and SGOL2 are expressed in mouse germ cells, and
SGOL1-depleted oocytes also show meiotic defects [135, 136].
During metaphase II, SGOL2 relocates in a tension-dependent
way to the centromeres in mouse spermatocytes and oocytes [115,
135]. In the absence of Sgo1, fission yeast sister chromatids co-
segregate to the same pole, implying that monopolar attachment is
intact, but they start to separate precociously during anaphase I.
Thus because Rec8 is no longer protected without Sgo1 during
meiosis I, the sister chromatids separate prematurely in anaphase I.
The finding that shugoshins protect centromeric cohesion by
recruiting PP2A suggests that the phosphorylation of a protein is
needed for Rec8 cleavage. In mitotic yeast cells, cohesin cleavage is
promoted through phosphorylation of Scc1 by PLK (Cdc5 in

yeast), which also participates in the phosphorylation of Rec8 [36].
Replacement of alanine for Rec8 residues that are thought to be
phosphorylated by Cdc5 has no significant effect on the kinetics of
cohesin cleavage at meiosis I [137]. Recent work has shown that
casein kinase 1δ/ε (CK1δ/ε), Hrr25 in yeast, and Dbf4-dependent
Cdc7 kinase (DDK) are essential for Rec8 cleavage, not Cdc5
[138]. Investigators have proposed that Hrr25- and DDK-
dependent phosphorylation of Rec8 promotes cohesin cleavage in
meiosis I, whereas dephosphorylation of Rec8 by PP2A bound to
Sgo1 protects it from separase at centromeres.
3.5 Characterization The characterization of mice deficient in meiosis-specific subunits

of Cohesin Subunit has helped us to understand the function of these proteins in mam-
Mutants malian meiosis. Both male and female SMC1β-deficient mice are
sterile and show defects in SC formation and premature loss of
sister chromatid cohesion [139]. SMC1β-deficient spermatocytes
undergo pachytene arrest, whereas mutant oocytes reveal prema-
ture loss of cohesion at metaphase II. REC8-deficient male and
female mice are also sterile and display severe defects in synapsis
and sister chromatid cohesion, but the phenotypes are different
than those of SMC1β mutant mice [140]. SC formation occurs
aberrantly in REC8 mutant spermatocytes between sister chroma-
tids instead of between homologous chromosomes. AE-like struc-
tures are formed, even though synapsis does not occur correctly.
Rec8 deletion mutants in budding yeast and C. elegans also cause
sister chromatids to lose cohesion and to separate early, yielding
aneuploid gametes [82, 121]. However, in fission yeast Rec8
mutants lose cohesion only at centromeres because Rad21 pro-
vides cohesion along sister chromatid arms [83]. RAD21L-
deficient male mice show a defect in chromosome synapsis at
prophase I, which leads to meiotic arrest at a zygotene-like stage
[99]. Deficient females, however, are initially fertile but develop an
age-dependent sterility.
Absence of SYCP2 or SYCP3 in mice results in a sexually
dimorphic phenotype: males are sterile, and females are subfertile
[141, 142]. Males show a disruption in chromosomal synapsis and
meiotic arrest in prophase I, but females have reduced litter size
and embryo death due to chromosome mis-segregation from
aneuploid oocytes. Sycp3-deficient male mice show defects in AE
formation, chromosomal synapsis, and SC assembly [141]. A null
mutation of Sycp1 causes sterility in homozygous male and female
mice. Most of Sycp1-deficient spermatocytes display defects in mei-
otic recombination and arrest at the pachytene stage, and mutant
ovaries reveal a paucity of oocytes and growing follicles [143].
Male Fkbp6-/- mice are sterile, whereas mutant females are fertile.
The mutant spermatocytes show severe defects in pairing and syn-
apsis and arrest at pachytene of prophase I [118]. Similar to
Fkbp6-null mice, Nek1-null male mice show severely impaired

fertility consistent with an absence of epididymal sperm and a
reduction in testis weight and size [119]. Holloway et al. also dem-
onstrated that Nek1-null mice show defects in cohesin SMC3
removal during diplonema, suggesting that NEK1 plays a role in
cohesin unloading at the end of prophase I.
4 Human Health and Disease
4.1 Cohesinopathies Human diseases caused by mutations in primary genes associated

with the cohesin network are termed cohesinopathies. All the
cohesinopathies that have been identified manifest as multisystem
developmental disorders, but they have distinct phenotypes.
Although mutations in the cohesin network might be expected to
generate defects in chromosome segregation and/or the ability to
repair DNA, mutations of this nature are probably lethal and have
not been reported. Instead, cohesinopathies are characterized by a
variety of developmental defects, including growth and mental
retardation, limb deformities, and craniofacial anomalies. These
phenotypes are consistent with a role for cohesins in gene expres-
sion during embryogenesis. Although downregulating cohesin suf-
ficiently to cause significant sister chromatid cohesion defects is
lethal in eukaryotes, the mechanism of action by which cohesin
affects developmental processes appears to be through a nonca-
nonical role as a regulator of gene expression and other genomic
processes. The molecular mechanisms underlying the changes in
gene expression that result in cohesinopathies are not well known.
Mechanisms have been proposed, such as actions of cohesin
in transcriptional activation, transcriptional repression, transcript
termination, and long-distance enhancer–promoter interactions,
none of which are mutually exclusive.
4.2 Cornelia de Cornelia de Lange syndrome (CdLS) is a dominantly inherited,

Lange Syndrome multisystem developmental disorder characterized by classic facial
anomalies, upper extremity malformations, hirsutism, cardiac
defects, growth and cognitive retardation, and gastrointestinal
abnormalities. Behavioral and cognitive defects display a wide range
of severity, as do limb malformations, which can range from small
digits to both upper and lower limb defects. CdLS is caused by point
mutations or small deletions/insertions in one of the two alleles of
SMC1, SMC3, or most commonly, NIPBL (Nipped-B-like and the
human orthologue of SCC2) [144–147]. Mutations in NIPBL, the
vertebrate homologue of the yeast Scc2 protein and a regulator of
cohesin loading and unloading, are responsible for approximately
50 % of cases of CdLS [144, 145, 148]. Two other mutations in
SMC1 and SMC3 were shown to result in an X-linked form of CdLS
that is milder than the syndrome caused by NIPBL mutations [146].
The mutations in the SMC proteins have been identified within the
coiled coil of the ATPase head domain and near the interface of the
coiled coil with the hinge domain [147]. Mutations in this region
disrupt DNA binding and ATP hydrolysis involved in loading
cohesins. Mutations in NIPBL have been identified throughout
the coding and noncoding regions of the gene. Alternative splicing
of NIPBL is consistent with multiple transcripts detected by
Northern blot analysis, and some types of mutations tend to result
in more severe forms of CdLS [144, 148]. Mutations have been
identified only in the context of the genomic copy and may affect
particular splice variants, potentially affecting the severity of the
disease phenotype.
The mutations in the SMC proteins could weaken interactions
between cohesin subunits or between chromatin and cohesin.
However, the mutations most likely do not abolish complex for-
mation or chromatin association completely because patients do
not exhibit severe defects in chromosome cohesion, DNA damage
response, or chromosome segregation [149, 150]. Sister chroma-
tid cohesion has been reported to be mildly affected in cell lines
derived from individuals with mutations in NIPBL [149], but no
defects in precocious sister chromatid separation have been
observed in cells with a mutation in SMC1 or SMC3 [151]. CdLS
mutations could affect the dynamics of cohesin subunit–chromatin
interaction, resulting in mild destabilization of the complex on
chromatin without affecting the overall function of the complex
for cohesion. Interestingly, NIPBL expression in human embry-
onic tissue sections is consistent with affected tissues and organs
seen in patients [145]. Molecular studies of cohesins in this disease
will help elucidate the defects underlying the mechanism of the
mutated cohesins.
A mouse model of CdLS has been developed in which the mice
are heterozygous for an Nipbl mutation [152]. These mice show
similar defects that are characteristic of the syndrome, including
small size, craniofacial anomalies, delayed bone maturation, micro-
brachycephaly, behavioral disturbances, and high mortality during
the early weeks of postnatal life. The Nipbl deficiency in heterozy-
gous mice leads to small but significant transcriptional dysregulation
of many genes. Expression changes at the protocadherin β locus,
which encodes synaptic cell adhesion molecules for neural tube and
CNS development, as well as other loci, support the notion that
NIPBL influences long-range chromosomal regulatory interactions.
Although this model has proven to be beneficial in studying CdLS,
closer scrutiny of cohesins in the disease is still needed.
4.3 Roberts Roberts syndrome and SC phocomelia are rare, recessively inherited,
Syndrome/SC multisystem disorders involving craniofacial, cardiac, limb, other
Phocomelia systemic abnormalities, and neurocognitive dysfunction. Roberts syn-
drome and SC phocomelia are similar disorders, but SC phocomelia
represents a milder phenotype of Roberts syndrome. Chromosomal

features in metaphase spreads of patients with Roberts syndrome
reveal a lack of cohesion in heterochromatic areas around centromeres
and at the distal region on the long arm of the Y chromosome, known
as heterochromatin repulsion or puffing or premature centromere
separation [153, 154]. Mitotic chromosomes have a railroad track-
like appearance; although this resembles a cohesion defect, it does not
appear to cause chromosome segregation defects. Roberts syndrome/
SC phocomelia is caused by a mutation in both alleles of ESCO2, the
human orthologue of yeast ECO1. In most cases the mutations are
truncating, but at least two mutations that disrupt the acetyltransfer-
ase activity of ESCO2 have been identified [155]. The majority of
mutations identified result in low or undetectable levels of mRNA
compared with wild-type ESCO2 expression. Although there are
two genes that encode ECO1 paralogues, ESCO1 and ESCO2, only
ESCO2 has been implicated in Roberts syndrome and SC phocome-
lia. This is interesting because the ESCO1 and ESCO2 genes share a
C-terminal acetyltransferase domain and a zinc-finger motif but differ
in their N-termini [156].
Although ESCO2 is required for the establishment of sister
chromatid cohesion, processivity of DNA replication forks in cells
from patients with Roberts syndrome is reduced, suggesting a role
for ESCO2 in replication-coupled cohesion [73]. Decreased
ESCO2 activity may lead to some loss of cohesion that manifests as
heterochromatic repulsion, but there may be sufficient protection
of centromeric cohesion through the activity of shugoshin and
PP2A so that chromosome segregation is not disturbed. As in
CdLS, ESCO2 is expressed in human embryonic tissues in a pat-
tern that is consistent with the systems and organs affected in
patients with this syndrome [155].
4.4 PDS5 Two copies of the Pds5 gene, Pds5A and Pds5B, are found in
Deficiencies mammals and differ in expression [55]. Both Pds5A- and Pds5B-
deficient mice are born with multiple congenital abnormalities,
including growth retardation, cleft palate, and congenital heart
defects, similar to the abnormalities found in humans with CdLS,
and they die at birth [56, 157]. Surprisingly, Pds5B-deficient
mouse embryonic fibroblasts lack defects in sister chromatid
cohesion, but expression is detected in postmitotic neurons in
the brain [157], suggesting an alternate role for cohesins. This
expression pattern is similar to that of Smc1, Rad21, Pds5B, and
Smc3 in zebrafish [158], and in conjunction with the neurologi-
cal phenotypes of the mutants the pattern suggests a crucial role
for cohesin in the development and migration of neurons. Because
this regulatory cohesin protein has not been well characterized in
the human disease, examining these deficiencies more closely
would be beneficial to better understand the mechanisms under-
lying PDS5A and PDS5B function.
4.5 α-Thalassemia/ α-Thalassemia/mental retardation syndrome, X-linked (ATRX), is

Mental Retardation a multisystem disorder of postnatal growth deficiency, mental
Syndrome, X-Linked retardation, microcephaly, dysmorphic craniofacial features, genital
abnormalities in males, seizures, and a mild form of hemoglobin H
disease. ATRX is caused by mutations in the ATRX gene on the X
chromosome and was recently found to also lead to a cohesion
defect in ATRX-depleted mammalian cells. The ATRX gene
encodes a chromatin remodeling enzyme that is highly enriched at
pericentromeric heterochromatin in mouse and human cells and
associates with heterochromatin protein 1α (HP1α), just like
NIPBL [159]. In mammalian cells, defects in sister chromatid
cohesion and chromosome congression at the metaphase plate and
mitotic defects were described. Defects in the ATRX gene are
thought to result from perturbed cohesin targeting or loading/
unloading. ATRX is believed to play a dual role in the regulation of
cohesion during mitosis and in the control of gene expression in
interphase, which is reminiscent of cohesin complex function.
Investigators have recently found that ATRX is required for nor-
mal recruitment of cohesin in mouse brain cells and alters expres-
sion of imprinted genes in the postnatal brain [160]. Therefore,
ATRX along with cohesin may regulate expression of this imprinted
gene network by controlling higher order chromatin structure.
Defects in the ATRX gene disrupt the cohesin targeting and/or
loading/unloading, resulting in ATRX syndrome phenotypes.
4.6 Warsaw Only one patient with Warsaw breakage syndrome has been
Breakage Syndrome reported who displayed severe microcephaly, pre- and postnatal
growth retardation, and abnormal skin pigmentation. The patient
displayed two mutations in the ChlR1 helicase, also called DDX11:
a splice-site mutation in intron 22 of the maternal allele and a
three-base pair deletion in exon 26 of the paternal allele [161].
The maternal allele mutation leads to a deletion of the last 10 base
pairs of exon 22 from the cDNA, and the paternal allele mutations
result in deletion of a highly conserved lysine residue in the ChlR1
protein. Cells from this patient reveal chromosomal instability
characterized by sister cohesion defects, chromosomal breakage,
and sensitivity to DNA cross-linking agents and topoisomerase
inhibitors. Investigators have suggested that Warsaw breakage
syndrome represents a unique disease with cellular features of both
Fanconi anemia and Roberts syndrome, but with a distinct clinical
phenotype. Other patients have yet to be identified with these
same characteristics, and the defects underlying the ChlR1 muta-
tions have yet to be revealed.
4.7 Maternal Aging Chromosome abnormalities represent not only the leading cause
and Chromosome of birth defects in humans but also the major cause of pregnancy
Segregation loss. Approximately 0.2–0.3 % of newborn infants are trisomic, and a
majority of these errors result from fertilization of a chromosomally
abnormal egg by a normal sperm (reviewed in ref. 162). For this

reason, attention has focused on why human female meiosis is so
error prone. It is widely understood that the number of pregnan-
cies involving trisomies increases drastically among women in their
40s to 35 %, compared with women in their 20s, in whom the rate
is 2–3 % (reviewed in ref. 163). Little is known about the basis of
this increased frequency of aneuploidy with age, but cohesins are
becoming increasingly implicated because these complexes are
essential for proper chromosome segregation in mitosis and meio-
sis. Because S phase takes place during fetal development in the
oocyte and cell division does not occur until resumption of meiosis
beginning at puberty, cohesins may in part be responsible for these
errors. Sites of DNA crossover are also established decades before
they function as physical mediators of chromosome segregation
(reviewed in ref. 163). The correlation between age and aneu-
ploidy in humans has been postulated to result from age-related
weakening of cohesion.
SMC1β-deficient female mice provided the first direct evidence
of an age-related decline in chromosome cohesion in mammalian
oocytes [139]. Revenkova et al. demonstrated that SMC1β-deﬁcient
mice in both sexes were sterile, but male meiosis was blocked in
pachynema, whereas in females meiosis progressed until metaphase
II. AEs are markedly shortened, chromatin extends further from
the AEs, chromosome synapsis is incomplete, sister chromatid
cohesion at chromosome arms and centromeres are lost prema-
turely, and crossovers are absent or reduced owing to this defi-
ciency. A recent study observed that when the SMC1β gene is
deleted in mice after the neonatal period and the protein is pro-
duced only during fetal development, fertility is not affected [164].
This finding suggests that meiotic cohesin is sufficiently robust that
once cohesion is established in fetal oocytes, little or no turnover
of the cohesin protein occurs until fertilization at reproductive
maturity. The pronounced age effect observed in SMC1β-deficient
mice suggests that the cause may not be related to recombination
itself, but instead to defective cohesion [165]. Weakened cohesion
in these mice may accelerate the normal aging process, but severe
abnormalities occur if cohesin complexes are absent [139]. Loss of
cohesion may explain human age-related nondisjunction, but it
raises a question about the fate of cohesins during prophase I arrest
in women.
The possible association between age-related degradation of
cohesion and increasing rate of aneuploidy was also examined in
older, naturally aged female mice [166, 167]. Centromere cohesion
was assessed by examining the distances between sister kineto-
chores in old compared to young oocytes [166]. Studies of meta-
phase I and II oocytes revealed an increase in distance between
sister kinetochores from old compared to young mice, suggesting
an age-related loss of centromere cohesion. Immunofluorescence
staining of chromosome-associated REC8 was also analyzed, and

levels were significantly reduced in old compared to young oocytes
[166]. Thus, loss of cohesion with age could predispose oocytes to
meiotic errors involving the premature separation of homologues
and sister chromatids. In a similar study, 14-month-old female
mice showed increased interkinetochore distances, reduction in
REC8 staining, and increases in anaphase defects compared to
2-month-old mice [167]. An age-related depletion of SGO2, a
protein necessary for preventing degradation of centromere cohe-
sin at anaphase I, was also observed, suggesting another cause of
aneuploidy. These studies provide a plausible explanation for non-
disjunction events, including not only abnormalities involving
homologous chromosomes at the first meiotic division but also
abnormalities involving mis-segregation of sister chromatids.
Human oogenesis is an extremely error-prone process, which
leads to a high percentage of aneuploid oocytes compared to sper-
matocytes. The percentage of aneuploid oocytes increases with
age, known as the “maternal age effect,” and loss of sister chroma-
tid cohesion has been postulated as a culprit for this phenomenon
[168]. A recent study has shed light on cohesins in human oocytes
and provides surprising counterpoints to the mouse data above
[117]. In oocytes from women aged 18 to 34 years, no age-related
changes were identifiable in immunolocalization patterns of
REC8, SMC3, STAG3, or SMC1β, or in levels of SMC1β gene
expression. Direct evidence linking age-related cohesin degrada-
tion to human oogenesis is therefore lacking, and the physiologi-
cal basis of maternal age-related aneuploidy is unknown, although
loss of cohesion could still be an important contributing factor.
5 Conclusions
Cumulative studies from many model organisms have established

that cohesins play a key role in sister chromatid cohesion and
the maintenance of genome integrity during cell division. During
meiosis, distinct cohesin complexes, composed of different sub-
units including those that are meiosis-specific, regulate chromo-
some dynamics and are essential for normal germ cell development
and precise chromosome segregation. The recent discovery that
cohesins are involved with the replication machinery and other fac-
tors necessary for proper DNA replication during mitosis and mei-
osis barely touches the surface in shedding light on these complex
proteins. The question of how cohesin complexes associate with
DNA has yet to be answered. Debate over the different models
continues, and conclusive data are needed to settle the issue. Only
in the past several years have cohesinopathies been recognized and
mutations in the cohesin subunits characterized. The maternal age
effect is unresolved, but it is thought to be due to loss of cohesion
between sister chromatids with age, leading to premature chromo-

some separation and ultimately to aneuploidy. Although the roles
of cohesins and their mechanisms of action have yet to be fully
elucidated, research continues to move forward and progress so far
has been remarkable.
Acknowledgements
This work was supported in part by the NIH (1R01GM106262 to

KMB). We thank Dr. Soumya Rudra for critical reading of the
manuscript. We apologize to any authors/researchers whose con-
tributions we may have overlooked.
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Chapter 11

The Roles of Cohesins in Mitosis, Meiosis,

During the S phase of the cell cycle, DNA replication generates a

crossovers form between paired homologous chromosomes, called

ter chromatids begin to separate to opposite poles via kinetochore

2.1 What Is It is critical that cohesion between sister chromatids be maintained

Scc/ Scc/ Scc/

A model of the cohesin complex has been frequently proposed

the metaphase plate. Aurora B/Ipl1 plays a crucial role in promot-

Ring Model Handcuff Model

form of Scc1 resistant to Esp1 are unable to separate [2]. Conversely,

2.5 Role of Cohesins Mutations and deletions in replication machinery components

ChlR1 results in abnormal sister cohesion and a delay at prometa-

transduction pathway and are important for survival after irradia-

Although the process of meiosis is similar to mitosis, haploid gam-

sister chromatids are separated into four different nuclei by two

anaphase I. Centromeric cohesion in meiosis II is essential to ensure

cohesion at the centromeres ensures proper segregation at the

SMC SMCα SMC SMCα

RAD SA/SA RADL STAG

SMC SMCβ SMC SMCβ SMC SMCβ

RAD STAG RADL STAG REC STAG

dispensable for these functions but it is required for centromeric

quency [102]. In yeast, frequent errors in meiosis II, rather than

3.3 Specific Events Prophase I is prolonged in mammalian meiosis, and it is divided

3.3.1 Leptonema During prophase I in spermatocytes, cohesin subunits are observed

Based on the studies mentioned here, several different cohesin

3.3.5 Metaphase I In metaphase I mammalian spermatocytes, STAG3 is seen as dis-

studies in rodent surface-spread spermatocytes indicated that

anaphase I, cohesins are no longer seen at the arms of sister chroma-

3.3.9 Synaptonemal One component of the CE unique to mammals is FK506-binding

3.4 Loss of Cohesion Destruction of cohesion distal to chiasmata is mediated by the

promoted through phosphorylation of Scc1 by PLK (Cdc5 in

3.5 Characterization The characterization of mice deficient in meiosis-specific subunits

Fkbp6-null mice, Nek1-null male mice show severely impaired

4 Human Health and Disease

4.1 Cohesinopathies Human diseases caused by mutations in primary genes associated

4.2 Cornelia de Cornelia de Lange syndrome (CdLS) is a dominantly inherited,

represents a milder phenotype of Roberts syndrome. Chromosomal

4.5 α-Thalassemia/ α-Thalassemia/mental retardation syndrome, X-linked (ATRX), is

abnormal egg by a normal sperm (reviewed in ref. 162). For this

staining of chromosome-associated REC8 was also analyzed, and

Cumulative studies from many model organisms have established

between sister chromatids with age, leading to premature chromo-

This work was supported in part by the NIH (1R01GM106262 to

41. Nakajima M, Kumada K, Hatakeyama K, chromatid cohesion in vertebrates. Mol Cell

Ctf18-Dcc1-Ctf8-replication factor C complex Atm-dependent and independent responses

double-strand break to double-Holliday 99. Herran Y, Gutierrez-Caballero C, Sanchez-

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Scc/ Scc/ Scc/

RAD SA/SA RADL STAG

RAD STAG RADL STAG REC STAG