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MCM8IP activates the MCM8-9 helicase to promote DNA synthesis and homologous recombination upon DNA damage

Author

Listed:
  • Jen-Wei Huang

    (Columbia University Irving Medical Center)

  • Ananya Acharya

    (Università della Svizzera italiana
    ETH Zurich)

  • Angelo Taglialatela

    (Columbia University Irving Medical Center)

  • Tarun S. Nambiar

    (Columbia University Irving Medical Center)

  • Raquel Cuella-Martin

    (Columbia University Irving Medical Center)

  • Giuseppe Leuzzi

    (Columbia University Irving Medical Center)

  • Samuel B. Hayward

    (Columbia University Irving Medical Center)

  • Sarah A. Joseph

    (Columbia University Irving Medical Center)

  • Gregory J. Brunette

    (University of Pittsburgh School of Medicine)

  • Roopesh Anand

    (Università della Svizzera italiana)

  • Rajesh K. Soni

    (Columbia University Irving Medical Center)

  • Nathan L. Clark

    (University of Utah)

  • Kara A. Bernstein

    (University of Pittsburgh School of Medicine)

  • Petr Cejka

    (Università della Svizzera italiana
    ETH Zurich)

  • Alberto Ciccia

    (Columbia University Irving Medical Center)

Abstract

Homologous recombination (HR) mediates the error-free repair of DNA double-strand breaks to maintain genomic stability. Here we characterize C17orf53/MCM8IP, an OB-fold containing protein that binds ssDNA, as a DNA repair factor involved in HR. MCM8IP-deficient cells exhibit HR defects, especially in long-tract gene conversion, occurring downstream of RAD51 loading, consistent with a role for MCM8IP in HR-dependent DNA synthesis. Moreover, loss of MCM8IP confers cellular sensitivity to crosslinking agents and PARP inhibition. Importantly, we report that MCM8IP directly associates with MCM8-9, a helicase complex mutated in primary ovarian insufficiency, and RPA1. We additionally show that the interactions of MCM8IP with MCM8-9 and RPA facilitate HR and promote replication fork progression and cellular viability in response to treatment with crosslinking agents. Mechanistically, MCM8IP stimulates the helicase activity of MCM8-9. Collectively, our work identifies MCM8IP as a key regulator of MCM8-9-dependent DNA synthesis during DNA recombination and replication.

Suggested Citation

  • Jen-Wei Huang & Ananya Acharya & Angelo Taglialatela & Tarun S. Nambiar & Raquel Cuella-Martin & Giuseppe Leuzzi & Samuel B. Hayward & Sarah A. Joseph & Gregory J. Brunette & Roopesh Anand & Rajesh K., 2020. "MCM8IP activates the MCM8-9 helicase to promote DNA synthesis and homologous recombination upon DNA damage," Nature Communications, Nature, vol. 11(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-16718-3
    DOI: 10.1038/s41467-020-16718-3
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    Cited by:

    1. Jessica D. Tischler & Hiroshi Tsuchida & Rosevalentine Bosire & Tommy T. Oda & Ana Park & Richard O. Adeyemi, 2024. "FLIP(C1orf112)-FIGNL1 complex regulates RAD51 chromatin association to promote viability after replication stress," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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