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BRCA2 associates with MCM10 to suppress PRIMPOL-mediated repriming and single-stranded gap formation after DNA damage

Author

Listed:
  • Zhihua Kang

    (Rutgers Cancer Institute of New Jersey)

  • Pan Fu

    (Rutgers Cancer Institute of New Jersey
    Children’s Hospital of Fudan University)

  • Allen L. Alcivar

    (Rutgers Cancer Institute of New Jersey
    Bristol-Myers Squibb Company)

  • Haiqing Fu

    (National Cancer Institute)

  • Christophe Redon

    (National Cancer Institute)

  • Tzeh Keong Foo

    (Rutgers Cancer Institute of New Jersey)

  • Yamei Zuo

    (Rutgers Cancer Institute of New Jersey)

  • Caiyong Ye

    (Rutgers Cancer Institute of New Jersey
    Soochow University)

  • Ryan Baxley

    (University of Minnesota)

  • Advaitha Madireddy

    (Rutgers Cancer Institute of New Jersey)

  • Remi Buisson

    (Massachusetts General Hospital Cancer Center and Harvard Medical School
    University of California Irvine)

  • Anja-Katrin Bielinsky

    (University of Minnesota)

  • Lee Zou

    (Massachusetts General Hospital Cancer Center and Harvard Medical School)

  • Zhiyuan Shen

    (Rutgers Cancer Institute of New Jersey)

  • Mirit I. Aladjem

    (National Cancer Institute)

  • Bing Xia

    (Rutgers Cancer Institute of New Jersey)

Abstract

The BRCA2 tumor suppressor protects genome integrity by promoting homologous recombination-based repair of DNA breaks, stability of stalled DNA replication forks and DNA damage-induced cell cycle checkpoints. BRCA2 deficient cells display the radio-resistant DNA synthesis (RDS) phenotype, however the mechanism has remained elusive. Here we show that cells without BRCA2 are unable to sufficiently restrain DNA replication fork progression after DNA damage, and the underrestrained fork progression is due primarily to Primase-Polymerase (PRIMPOL)-mediated repriming of DNA synthesis downstream of lesions, leaving behind single-stranded DNA gaps. Moreover, we find that BRCA2 associates with the essential DNA replication factor MCM10 and this association suppresses PRIMPOL-mediated repriming and ssDNA gap formation, while having no impact on the stability of stalled replication forks. Our findings establish an important function for BRCA2, provide insights into replication fork control during the DNA damage response, and may have implications in tumor suppression and therapy response.

Suggested Citation

  • Zhihua Kang & Pan Fu & Allen L. Alcivar & Haiqing Fu & Christophe Redon & Tzeh Keong Foo & Yamei Zuo & Caiyong Ye & Ryan Baxley & Advaitha Madireddy & Remi Buisson & Anja-Katrin Bielinsky & Lee Zou & , 2021. "BRCA2 associates with MCM10 to suppress PRIMPOL-mediated repriming and single-stranded gap formation after DNA damage," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26227-6
    DOI: 10.1038/s41467-021-26227-6
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    References listed on IDEAS

    as
    1. Thomas A. Guilliam & Nigel C. Brissett & Aaron Ehlinger & Benjamin A. Keen & Peter Kolesar & Elaine M. Taylor & Laura J. Bailey & Howard D. Lindsay & Walter J. Chazin & Aidan J. Doherty, 2017. "Molecular basis for PrimPol recruitment to replication forks by RPA," Nature Communications, Nature, vol. 8(1), pages 1-14, August.
    2. Haijuan Yang & Qiubai Li & Jie Fan & William K. Holloman & Nikola P. Pavletich, 2005. "The BRCA2 homologue Brh2 nucleates RAD51 filament formation at a dsDNA–ssDNA junction," Nature, Nature, vol. 433(7026), pages 653-657, February.
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    Cited by:

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    2. Tanay Thakar & Ashna Dhoonmoon & Joshua Straka & Emily M. Schleicher & Claudia M. Nicolae & George-Lucian Moldovan, 2022. "Lagging strand gap suppression connects BRCA-mediated fork protection to nucleosome assembly through PCNA-dependent CAF-1 recycling," Nature Communications, Nature, vol. 13(1), pages 1-19, December.

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