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Role for BLM in replication-fork restart and suppression of origin firing after replicative stress

Nature Structural & Molecular Biology volume 14, pages 677–679 (2007)Cite this article

Abstract

Mutations in BLM give rise to Bloom's syndrome, a genetic disorder associated with cancer predisposition and chromosomal instability. Using a dual-labeling system in isolated chromosome fibers, we show that the BLM protein is required for two aspects of the cellular response to replicative stress: efficient replication-fork restart and suppression of new origin firing. These functions require the helicase activity of BLM and the Thr99 residue targeted by stress-activated kinases.

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Figure 1: BLM is required for efficient replication-fork restart after replication blockade.
Figure 2: The ATR kinase target residue in BLM, Thr99, is required for efficient replication-fork restart and to suppress new origin firing.

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Acknowledgements

We thank members of the CR-UK Genome Integrity Group for helpful discussions, N. Ellis (University of Chicago), and M. Sanz and J. German (Cornell University Medical School, New York) for the wild-type BLM- and BLM-K695T–expressing GM08505 cells, P. McHugh, K. Hanada, C. Bachrati and L. Wu for useful comments on the manuscript, and P. White for preparation of the manuscript. This work was supported by Cancer Research UK.

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Authors and Affiliations

  1. Cancer Research UK Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK

    Sally L Davies, Phillip S North & Ian D Hickson

Authors
  1. Sally L Davies
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  2. Phillip S North
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  3. Ian D Hickson
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Contributions

Experiments were designed by S.L.D., P.S.N. and I.D.H., and performed by S.L.D. and P.S.N. S.L.D. and I.D.H. interpreted data and wrote the manuscript.

Corresponding author

Correspondence to Ian D Hickson.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

BS cells are hypersensitive to drugs that inhibit DNA replication. (PDF 59 kb)

Supplementary Fig. 2

BLM is required for efficient replication-fork restart following replication blockade. (PDF 61 kb)

Supplementary Fig. 3

The active site lysine (Lys695) and the Thr99 target site for ATR are required for cell survival after replication blockade. (PDF 36 kb)

Supplementary Fig. 4

Expression of BLM proteins in transfectred BS cells. (PDF 114 kb)

Supplementary Fig. 5

The active site of BLM is required fro suppression of new origin firing. (PDF 27 kb)

Supplementary Methods (PDF 117 kb)

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Davies, S., North, P. & Hickson, I. Role for BLM in replication-fork restart and suppression of origin firing after replicative stress. Nat Struct Mol Biol 14, 677–679 (2007). https://doi.org/10.1038/nsmb1267

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