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

Nat Commun. 2017 Jul 17;8:15983. doi: 10.1038/ncomms15983.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anaphase
  • BRCA2 Protein / genetics*
  • Cell Line, Tumor
  • Chromosome Segregation / genetics*
  • DNA / metabolism*
  • DNA Damage*
  • DNA Replication*
  • DNA-Binding Proteins / genetics*
  • Endonucleases / genetics*
  • HeLa Cells
  • Humans
  • Mitosis

Substances

  • BRCA2 Protein
  • BRCA2 protein, human
  • DNA-Binding Proteins
  • DNA
  • Endonucleases
  • MUS81 protein, human