Abstract
It is generally thought that the DNA-damage checkpoint kinases, ataxia-telangiectasia mutated (ATM) and ATM- and Rad3-related (ATR), work independently of one another. Here, we show that ATM and the nuclease activity of meiotic recombination 11 (Mre11) are required for the processing of DNA double-strand breaks (DSBs) to generate the replication protein A (RPA)-coated ssDNA that is needed for ATR recruitment and the subsequent phosphorylation and activation of Chk1. Moreover, we show that efficient ATM-dependent ATR activation in response to DSBs is restricted to the S and G2 cell cycle phases and requires CDK kinase activity. Thus, in response to DSBs, ATR activation is regulated by ATM in a cell-cycle dependent manner.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Ataxia Telangiectasia Mutated Proteins
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Cell Cycle Proteins / chemistry
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Cell Cycle Proteins / metabolism*
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Cell Cycle Proteins / physiology*
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Cell Cycle*
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Cell Line, Tumor
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Cell Nucleus / metabolism
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Checkpoint Kinase 1
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Cyclin-Dependent Kinases / metabolism
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DNA Damage*
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DNA-Binding Proteins / chemistry
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DNA-Binding Proteins / physiology*
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HeLa Cells
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Humans
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MRE11 Homologue Protein
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Nuclear Proteins / chemistry
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Nuclear Proteins / metabolism
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Phosphorylation
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Protein Kinases / metabolism
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Protein Serine-Threonine Kinases / chemistry
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Protein Serine-Threonine Kinases / metabolism*
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Protein Serine-Threonine Kinases / physiology*
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Replication Protein A / chemistry
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Replication Protein A / metabolism
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Tumor Suppressor Proteins / chemistry
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Tumor Suppressor Proteins / physiology*
Substances
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Cell Cycle Proteins
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DNA-Binding Proteins
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MRE11 protein, human
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NBN protein, human
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Nuclear Proteins
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Replication Protein A
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Tumor Suppressor Proteins
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Protein Kinases
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ATM protein, human
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ATR protein, human
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Ataxia Telangiectasia Mutated Proteins
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CHEK1 protein, human
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Checkpoint Kinase 1
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Protein Serine-Threonine Kinases
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Cyclin-Dependent Kinases
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MRE11 Homologue Protein