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MRE11 and EXO1 nucleases degrade reversed forks and elicit MUS81-dependent fork rescue in BRCA2-deficient cells

Author

Listed:
  • Delphine Lemaçon

    (Saint Louis University School of Medicine)

  • Jessica Jackson

    (Saint Louis University School of Medicine)

  • Annabel Quinet

    (Saint Louis University School of Medicine)

  • Joshua R. Brickner

    (Washington University School of Medicine)

  • Shan Li

    (Washington University School of Medicine)

  • Stephanie Yazinski

    (Harvard Medical School)

  • Zhongsheng You

    (Washington University School of Medicine)

  • Grzegorz Ira

    (Baylor College of Medicine)

  • Lee Zou

    (Harvard Medical School)

  • Nima Mosammaparast

    (Washington University School of Medicine)

  • Alessandro Vindigni

    (Saint Louis University School of Medicine)

Abstract

The breast cancer susceptibility proteins BRCA1 and BRCA2 have emerged as key stabilizing factors for the maintenance of replication fork integrity following replication stress. In their absence, stalled replication forks are extensively degraded by the MRE11 nuclease, leading to chemotherapeutic sensitivity. Here we report that BRCA proteins prevent nucleolytic degradation by protecting replication forks that have undergone fork reversal upon drug treatment. The unprotected regressed arms of reversed forks are the entry point for MRE11 in BRCA-deficient cells. The CtIP protein initiates MRE11-dependent degradation, which is extended by the EXO1 nuclease. Next, we show that the initial limited resection of the regressed arms establishes the substrate for MUS81 in BRCA2-deficient cells. In turn, MUS81 cleavage of regressed forks with a ssDNA tail promotes POLD3-dependent fork rescue. We propose that targeting this pathway may represent a new strategy to modulate BRCA2-deficient cancer cell response to chemotherapeutics that cause fork degradation.

Suggested Citation

  • Delphine Lemaçon & Jessica Jackson & Annabel Quinet & Joshua R. Brickner & Shan Li & Stephanie Yazinski & Zhongsheng You & Grzegorz Ira & Lee Zou & Nima Mosammaparast & Alessandro Vindigni, 2017. "MRE11 and EXO1 nucleases degrade reversed forks and elicit MUS81-dependent fork rescue in BRCA2-deficient cells," Nature Communications, Nature, vol. 8(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-01180-5
    DOI: 10.1038/s41467-017-01180-5
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