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Rad54 and Mus81 cooperation promotes DNA damage repair and restrains chromosome missegregation

Oncogene volume 35, pages 4836–4845 (2016)Cite this article

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Abstract

Rad54 and Mus81 mammalian proteins physically interact and are important for the homologous recombination DNA repair pathway; however, their functional interactions in vivo are poorly defined. Here, we show that combinatorial loss of Rad54 and Mus81 results in hypersensitivity to DNA-damaging agents, defects on both the homologous recombination and non-homologous DNA end joining repair pathways and reduced fertility. We also observed that while Mus81 deficiency diminished the cleavage of common fragile sites, very strikingly, Rad54 loss impaired this cleavage to even a greater extent. The inefficient repair of DNA double-strand breaks (DSBs) in Rad54−/−Mus81−/− cells was accompanied by elevated levels of chromosome missegregation and cell death. Perhaps as a consequence, tumor incidence in Rad54−/−Mus81−/− mice remained comparable to that in Mus81−/− mice. Our study highlights the importance of the cooperation between Rad54 and Mus81 for mediating DNA DSB repair and restraining chromosome missegregation.

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Acknowledgements

This work was supported by the Canadian Institute of Health Research (RH). We thank P McPherson and members of the RH laboratory for helpful discussions and critical reading of the manuscript. In addition, we thank S Hakem for editing the manuscript and R Kanaar for providing Rad54−/− mice.

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Author notes

  1. S El Ghamrasni and R Cardoso: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medical Biophysics, University of Toronto and Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada

    S El Ghamrasni, R Cardoso, L Li, K K N Guturi, A Hakem & R Hakem

  2. Department of Cellular and Molecular Medicine, Center for Chromosome Stability and Center for Healthy Ageing, University of Copenhagen, Panum Institute, Copenhagen, Denmark

    V A Bjerregaard, Y Liu & I D Hickson

  3. Department of Physiology, Yong Loo Lin School of Medicine and Tembusu College, National University of Singapore, Singapore

    S Venkatesan & M P Hande

  4. Department of Pharmaceutical Sciences, Division of Biomolecular Science, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada

    J T Henderson

  5. Department of pathology, University of Ontario Institute of Technology, Oshawa, Ontario, Canada

    O Sanchez

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Correspondence to R Hakem.

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Ghamrasni, S., Cardoso, R., Li, L. et al. Rad54 and Mus81 cooperation promotes DNA damage repair and restrains chromosome missegregation. Oncogene 35, 4836–4845 (2016). https://doi.org/10.1038/onc.2016.16

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