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

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. Soni, Nathan L. Clark, Kara A. Bernstein, Petr Cejka and Alberto Ciccia ()
Additional contact information
Jen-Wei Huang: Columbia University Irving Medical Center
Ananya Acharya: Università della Svizzera italiana
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
Alberto Ciccia: Columbia University Irving Medical Center

Nature Communications, 2020, vol. 11, issue 1, 1-18

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-16718-3

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