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.
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Acknowledgements
We are grateful to R.T. Abraham, R. Tsien and Y. Shiloh for providing valuable reagents and K. Dry for editorial help. This study was made possible by core infrastructure funding by Cancer Research UK and The Wellcome Trust, and was supported by Cancer Research UK, The AT Medical Research Trust, the Danish Cancer Society, the Danish National Research Foundation, the European Union Framework 6 Integrated Project Grant “DNA repair”, the European Science Foundation (EuroDYNA) and the John and Birthe Meyer Foundation.
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Jazayeri, A., Falck, J., Lukas, C. et al. ATM- and cell cycle-dependent regulation of ATR in response to DNA double-strand breaks. Nat Cell Biol 8, 37–45 (2006). https://doi.org/10.1038/ncb1337
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DOI: https://doi.org/10.1038/ncb1337
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