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ATM- and cell cycle-dependent regulation of ATR in response to DNA double-strand breaks

Nature Cell Biology volume 8, pages 37–45 (2006)Cite this article

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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Figure 1: Both ATM and ATR are required for IR-induced Chk1 phosphorylation.
Figure 2: ATM and Nbs1 are required for IR-induced ATR focus formation.
Figure 3: ATM and Nbs1 are required for IR-induced RPA focus formation.
Figure 4: Nuclease activity of Mre11 is required for IR-induced Chk1 phosphorylation and RPA focus formation.
Figure 5: Differential kinetics of recruitment and activation.
Figure 6: ATR recruitment, RPA focus formation and Chk1 phosphorylation are cell cycle regulated.
Figure 7: CDK activity is required for efficient IR-induced Chk1 phosphorylation and RPA-coated ssDNA generation.
Figure 8: Representation of IR-induced ATR activation and homologous recombination-mediated repair coordinated in an ATM and 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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  1. Ali Jazayeri and Jacob Falck: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Zoology, The Wellcome Trust and Cancer Research UK Gurdon Institute, Cambridge University, Tennis Court Road, Cambridge, CB2 1QN, UK

    Ali Jazayeri, Jacob Falck & Stephen P. Jackson

  2. KuDOS Pharmaceuticals Ltd., Cambridge Science Park, Milton Road, Cambridge, CB4 0WG, UK

    Ali Jazayeri, Graeme C. M. Smith & Stephen P. Jackson

  3. Institute of Cancer Biology and Centre for Genotoxic Stress Research, Danish Cancer Society, Copenhagen, DK-2100, Denmark

    Claudia Lukas, Jiri Bartek & Jiri Lukas

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  1. Ali Jazayeri
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Correspondence to Stephen P. Jackson.

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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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