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RAD18 transmits DNA damage signalling to elicit homologous recombination repair

Nature Cell Biology volume 11, pages 592603 (2009) | Download Citation

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Abstract

To maintain genome stability, cells respond to DNA damage by activating signalling pathways that govern cell-cycle checkpoints and initiate DNA repair. Cell-cycle checkpoint controls should connect with DNA repair processes, however, exactly how such coordination occurs in vivo is largely unknown. Here we describe a new role for the E3 ligase RAD18 as the integral component in translating the damage response signal to orchestrate homologous recombination repair (HRR). We show that RAD18 promotes homologous recombination in a manner strictly dependent on its ability to be recruited to sites of DNA breaks and that this recruitment relies on a well-defined DNA damage signalling pathway mediated by another E3 ligase, RNF8. We further demonstrate that RAD18 functions as an adaptor to facilitate homologous recombination through direct interaction with the recombinase RAD51C. Together, our data uncovers RAD18 as a key factor that orchestrates HRR through surveillance of the DNA damage signal.

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Acknowledgements

We thank T. Shiomi for HCT116 RAD18−/− cells, M. Yamaizumi for RAD18−/− MEFs, S. Akira for UBC13-deficient cells, H.Nagasawa for IRS3 and V79 cells, M. Jasin for U2OS cells with DR–GFP integration and pCBASce plasmids, B. P. Chen for NU7441 and J. Groenendyk for helping with the BIAcore system. J.C would like to thank all colleagues for discussions and technical assistance, and J. Wood for proofreading. This work was supported by grants from the National Institutes of Health to J.C., M.S.Y.H. is supported by the Anna Fuller Fund Fellowship and J.C. is a recipient of an Era of Hope Scholar award from the Department of Defense (a member of the Mayo Clinic Breast SPORE program).

Author information

Author notes

    • Hongtae Kim

    Current address: Department of Biological Science, Sungkyunkwan University, 300 Chunchundong, Suwon 440–746, Korea.

    • Xiaochun Yu

    Current address: Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan Medical School, 109 Zina Pitcher Place, BSRB 1520, Ann Arbor, MI 48109, USA.

Affiliations

  1. Department of Therapeutic Radiology, Yale University School of Medicine, P.O. Box 208040, New Haven, CT 06520, USA.

    • Jun Huang
    • , Michael S. Y. Huen
    • , Hongtae Kim
    •  & Junjie Chen
  2. Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada.

    • Charles Chung Yun Leung
    •  & J N Mark Glover

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Contributions

J.H. performed most of the experiments; J.H. and J.C. designed the experiments, analysed the data and wrote the manuscript; M.S.Y.H. performed the experiments shown in Fig. 2e; H.K. performed the experiments shown in Fig. S2a; C.C.Y.L. and J.N.M.G. performed the experiments shown in Fig. S2b, c and X.Y. generated the RNF8 and RAP80 knockout mice.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Junjie Chen.

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DOI

https://doi.org/10.1038/ncb1865

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