Letter | Published:

Regulation of DNA repair pathway choice in S and G2 phases by the NHEJ inhibitor CYREN

Nature volume 549, pages 548552 (28 September 2017) | Download Citation

Abstract

Classical non-homologous end joining1 (cNHEJ) and homologous recombination2 compete for the repair of double-stranded DNA breaks during the cell cycle. Homologous recombination is inhibited during the G1 phase of the cell cycle, but both pathways are active in the S and G2 phases. However, it is unclear why cNHEJ does not always outcompete homologous recombination during the S and G2 phases. Here we show that CYREN (cell cycle regulator of NHEJ) is a cell-cycle-specific inhibitor of cNHEJ. Suppression of CYREN allows cNHEJ to occur at telomeres and intrachromosomal breaks during the S and G2 phases, and cells lacking CYREN accumulate chromosomal aberrations upon damage induction, specifically outside the G1 phase. CYREN acts by binding to the Ku70/80 heterodimer and preferentially inhibits cNHEJ at breaks with overhangs by protecting them. We therefore propose that CYREN is a direct cell-cycle-dependent inhibitor of cNHEJ that promotes error-free repair by homologous recombination during cell cycle phases when sister chromatids are present.

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Acknowledgements

All data are archived at the Salk Institute. We thank E. Hendrickson, J. Stark and D. A. Ramsden for support and N. O’Reilly for peptide arrays. N.A. was supported by the Human Frontiers Science Program (LT000284/2013) and N.A. and A.M. by the Paul F. Glenn Center for Biology of Aging Research. J.M. is supported by a Larry Hillblom Foundation Fellowship Grant. S.J.B. is supported by a Wellcome Trust Senior Investigator Award and the Francis Crick Institute (Cancer Research UK), the UK Medical Research Council (FC0010048), and the Wellcome Trust (FC0010048). A.S. is supported by NIH (R01 GM102491), the NCI Cancer Center Support Grant P30 (CA014195), The Leona M. and Harry B. Helmsley Charitable Trust (#2012-PG-MED002), and Dr. Frederick Paulsen Chair/Ferring Pharmaceuticals. The Salk Institute Cancer Center Core Grant (P30CA014195), the NIH (R01GM087476, R01CA174942), the Donald and Darlene Shiley Chair, the Highland Street Foundation, the Fritz B. Burns Foundation and the Emerald Foundation support J.K.

Author information

Author notes

    • Marco Tognetti

    Present address: ETH Zurich, Institute of Biochemistry, Otto-Stern-Weg 3, 8093 Zurich, Switzerland.

    • Adriana Correia
    •  & Jiao Ma

    These authors contributed equally to this work.

Affiliations

  1. The Salk Institute for Biological Studies, 10010 North Torrey Pines Rd., La Jolla, California 92037, USA

    • Nausica Arnoult
    • , Adriana Correia
    • , Jiao Ma
    • , Anna Merlo
    • , Marco Tognetti
    • , Alan Saghatelian
    •  & Jan Karlseder
  2. Dsb Repair Metabolism Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK

    • Sara Garcia-Gomez
    • , Marija Maric
    •  & Simon J. Boulton
  3. Department of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA

    • Christopher W. Benner

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Contributions

Experiments were designed and performed by N.A. (all except Fig. 3c, Extended Data Figs 7b–d, 9), J.M. (Fig. 3c, Extended Data Figs 7b–d, 9), S.J.B. (Extended Data Figs 7a, 9), A.S. (Fig. 3c, Extended Data Figs 7b–d, 9), A.M. (Fig. 2a, b) and J.K. Experiments were performed by A.C. (Figs 2c, d, 3d, f–h, 4, Extended Data Figs 3c, 4, 6, 7f, 8), M.T. (Fig. 1b, c, f, Fig. 3b, Extended Data Figs 1, 3a, b, f, 5), S.G.G. (Extended Data Fig. 9) and M.M. (Extended Data Fig. 9), C.W.B. analysed data (Fig. 4b, c, Extended Data Fig. 8) and N.A. and J.K. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Jan Karlseder.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Supplementary information

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  1. 1.

    Supplementary Figure

    This file contains the uncropped blots.

  2. 2.

    Reporting Summary

About this article

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DOI

https://doi.org/10.1038/nature24023

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