Abstract
ATM (ataxia-telangiectasia mutated) is necessary for activation of Chk1 by ATR (ATM and Rad3-related) in response to double-stranded DNA breaks (DSBs) but not to DNA replication stress. TopBP1 has been identified as a direct activator of ATR. We show that ATM regulates Xenopus TopBP1 by phosphorylating Ser-1131 and thereby strongly enhancing association of TopBP1 with ATR. Xenopus egg extracts containing a mutant of TopBP1 that cannot be phosphorylated on Ser-1131 are defective in the ATR-dependent phosphorylation of Chk1 in response to DSBs but not to DNA replication stress. Thus, TopBP1 is critical for the ATM-dependent activation of ATR following production of DSBs in the genome.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Amino Acid Sequence
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Animals
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Ataxia Telangiectasia Mutated Proteins
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism*
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DNA Damage
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DNA Repair
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Enzyme Activation
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Humans
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Molecular Sequence Data
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Oocytes / chemistry
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Oocytes / metabolism
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Phosphorylation
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Sequence Alignment
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Serine / metabolism
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism*
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Xenopus Proteins / genetics
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Xenopus Proteins / metabolism*
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Xenopus laevis / physiology*
Substances
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ATRIP protein, Xenopus
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Carrier Proteins
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Cell Cycle Proteins
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DNA-Binding Proteins
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Recombinant Proteins
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TopBP1 protein, Xenopus
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Tumor Suppressor Proteins
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Xenopus Proteins
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Serine
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Atr protein, Xenopus
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ATM protein, human
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Ataxia Telangiectasia Mutated Proteins
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Protein Serine-Threonine Kinases