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

Author

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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)

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.

Suggested Citation

  • Xianning Lai & Ronan Broderick & Valérie Bergoglio & Jutta Zimmer & Sophie Badie & Wojciech Niedzwiedz & Jean-Sébastien Hoffmann & Madalena Tarsounas, 2017. "MUS81 nuclease activity is essential for replication stress tolerance and chromosome segregation in BRCA2-deficient cells," Nature Communications, Nature, vol. 8(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms15983
    DOI: 10.1038/ncomms15983
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    Cited by:

    1. Frederick Richards & Marta J. Llorca-Cardenosa & Jamie Langton & Sara C. Buch-Larsen & Noor F. Shamkhi & Abhishek Bharadwaj Sharma & Michael L. Nielsen & Nicholas D. Lakin, 2023. "Regulation of Rad52-dependent replication fork recovery through serine ADP-ribosylation of PolD3," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    2. Wezley C. Griffin & David R. McKinzey & Kathleen N. Klinzing & Rithvik Baratam & Achini Eliyapura & Michael A. Trakselis, 2022. "A multi-functional role for the MCM8/9 helicase complex in maintaining fork integrity during replication stress," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    3. Domagoj Vugic & Isaac Dumoulin & Charlotte Martin & Anna Minello & Lucia Alvaro-Aranda & Jesus Gomez-Escudero & Rady Chaaban & Rana Lebdy & Catharina Nicolai & Virginie Boucherit & Cyril Ribeyre & Ang, 2023. "Replication gap suppression depends on the double-strand DNA binding activity of BRCA2," Nature Communications, Nature, vol. 14(1), pages 1-19, December.

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