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Mre11 regulates CtIP-dependent double-strand break repair by interaction with CDK2

Nature Structural & Molecular Biology volume 19, pages 246252 (2012) | Download Citation

Abstract

Homologous recombination facilitates accurate repair of DNA double-strand breaks (DSBs) during the S and G2 phases of the cell cycle by using intact sister chromatids as sequence templates. Homologous recombination capacity is maximized in S and G2 by cyclin-dependent kinase (CDK) phosphorylation of CtIP, which subsequently interacts with BRCA1 and the Mre11–Rad50–NBS1 (MRN) complex. Here we show that, in human and mouse, Mre11 controls these events through a direct interaction with CDK2 that is required for CtIP phosphorylation and BRCA1 interaction in normally dividing cells. CDK2 binds the C terminus of Mre11, which is absent in an inherited allele causing ataxia telangiectasia–like disorder. This newly uncovered role for Mre11 does not require ATM activation or nuclease activities. Therefore, functions of MRN are not restricted to DNA damage responses but include regulating homologous recombination capacity during the normal mammalian cell cycle.

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Acknowledgements

The authors thank M. Weitzman (Salk Institute), P. Kaldis (A*STAR, Institute of Molecular and Cell Biology) and B. Sleckman (Washington University) for providing cell lines; J. Sekiguchi (University of Michigan) for providing ATM−/− mice; and M. Jasin (Memorial Sloan-Kettering Cancer Center) for providing DR-GFP plasmid. We thank T. Wilson, X. Yu, J. Sekiguchi, G. Dressler and C. Canman for helpful discussions regarding the manuscript. Support for this work was provided by US National Institutes of Health (NIH) grant R01-HL079118 (to D.O.F.), the Leukemia and Lymphoma Society (to D.O.F.), the University of Michigan Cancer Center Support Grant 5-P30-CA46592 (D.O.F.), NIH F32-GM087073 (J.B.) and NIH T32-AI007413 (E.S.).

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Affiliations

  1. Department of Pathology, The University of Michigan Medical School, Ann Arbor, Michigan, USA.

    • Jeffrey Buis
    • , Trina Stoneham
    • , Elizabeth Spehalski
    •  & David O Ferguson

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Contributions

J.B. planned and conducted all experiments except the two-hybrid and B-lymphocyte analyses, analyzed and interpreted data from all experiments and participated in writing the manuscript. T.S. conducted and interpreted the two-hybrid analyses. E.S. carried out the B lymphocyte western blot analysis from spleens of mice from complex breeds. D.O.F. participated in design of all experiments, analyses and interpretation of data and in writing of the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to David O Ferguson.

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DOI

https://doi.org/10.1038/nsmb.2212

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