MUS81 nuclease activity is essential for replication stress tolerance and chromosome segregation in BRCA2-deficient cells

Xianning Lai, Ronan Broderick, Valérie Bergoglio, Jutta Zimmer, Sophie Badie, Wojciech Niedzwiedz, Jean-Sébastien Hoffmann and Madalena Tarsounas ()
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Xianning Lai: Genome Stability and Tumourigenesis Group, The CR-UK/MRC Oxford Institute for Radiation Oncology, University of Oxford
Ronan Broderick: Institute of Cancer Research
Valérie Bergoglio: Cancer Research Center of Toulouse, Université de Toulouse, Inserm, CNRS, UPS, Equipe labellisée Ligue Contre le Cancer, Laboratoire d’excellence Toulouse Cancer
Jutta Zimmer: Genome Stability and Tumourigenesis Group, The CR-UK/MRC Oxford Institute for Radiation Oncology, University of Oxford
Sophie Badie: Genome Stability and Tumourigenesis Group, The CR-UK/MRC Oxford Institute for Radiation Oncology, University of Oxford
Wojciech Niedzwiedz: Institute of Cancer Research
Jean-Sébastien Hoffmann: Cancer Research Center of Toulouse, Université de Toulouse, Inserm, CNRS, UPS, Equipe labellisée Ligue Contre le Cancer, Laboratoire d’excellence Toulouse Cancer
Madalena Tarsounas: Genome Stability and Tumourigenesis Group, The CR-UK/MRC Oxford Institute for Radiation Oncology, University of Oxford

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: Abstract Failure to restart replication forks stalled at genomic regions that are difficult to replicate or contain endogenous DNA lesions is a hallmark of BRCA2 deficiency. The nucleolytic activity of MUS81 endonuclease is required for replication fork restart under replication stress elicited by exogenous treatments. Here we investigate whether MUS81 could similarly facilitate DNA replication in the context of BRCA2 abrogation. Our results demonstrate that replication fork progression in BRCA2-deficient cells requires MUS81. Failure to complete genome replication and defective checkpoint surveillance enables BRCA2-deficient cells to progress through mitosis with under-replicated DNA, which elicits severe chromosome interlinking in anaphase. MUS81 nucleolytic activity is required to activate compensatory DNA synthesis during mitosis and to resolve mitotic interlinks, thus facilitating chromosome segregation. We propose that MUS81 provides a mechanism of replication stress tolerance, which sustains survival of BRCA2-deficient cells and can be exploited therapeutically through development of specific inhibitors of MUS81 nuclease activity.

Date: 2017
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DOI: 10.1038/ncomms15983

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