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Identification of MCM8IP, an interactor of MCM8-9 and RPA1 that promotes homologous recombination and DNA synthesis in response to DNA damage

Jen-Wei Huang, Angelo Taglialatela, Ananya Acharya, Giuseppe Leuzzi, Tarun S. Nambiar, Raquel Cuella-Martin, Samuel B. Hayward, Gregory J. Brunette, Roopesh Anand, Rajesh K. Soni, Nathan L. Clark, Kara A. Bernstein, Petr Cejka, Alberto Ciccia
doi: https://doi.org/10.1101/751974
Jen-Wei Huang
1Department of Genetics and Development, Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA
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Angelo Taglialatela
1Department of Genetics and Development, Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA
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Ananya Acharya
2Institute for Research in Biomedicine, Università della Svizzera Italiana, Bellinzona, Switzerland
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Giuseppe Leuzzi
1Department of Genetics and Development, Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA
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Tarun S. Nambiar
1Department of Genetics and Development, Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA
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Raquel Cuella-Martin
1Department of Genetics and Development, Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA
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Samuel B. Hayward
1Department of Genetics and Development, Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA
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Gregory J. Brunette
3Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
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Roopesh Anand
2Institute for Research in Biomedicine, Università della Svizzera Italiana, Bellinzona, Switzerland
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Rajesh K. Soni
4Proteomics Shared Resource, Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA
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Nathan L. Clark
5Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA, USA
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Kara A. Bernstein
3Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
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Petr Cejka
2Institute for Research in Biomedicine, Università della Svizzera Italiana, Bellinzona, Switzerland
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Alberto Ciccia
1Department of Genetics and Development, Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA
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  • For correspondence: ac3685@cumc.columbia.edu
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ABSTRACT

Homologous recombination (HR) mediates the error-free repair of DNA double-strand breaks to maintain genomic stability. HR is carried out by a complex network of DNA repair factors. Here we identify C17orf53/MCM8IP, an OB-fold containing protein that binds ssDNA, as a novel 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 identify a direct interaction with MCM8-9, a putative helicase complex mutated in Primary Ovarian Insufficiency, that is crucial for MCM8IP’s ability to promote resistance to DNA damaging agents. In addition to its association with MCM8-9, MCM8IP also binds directly to RPA1. We show that the interactions of MCM8IP with both MCM8-9 and RPA are required to maintain replication fork progression in response to treatment with crosslinking agents. Collectively, our work identifies MCM8IP as a key regulator of DNA damage-associated DNA synthesis during DNA recombination and replication.

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Posted September 03, 2019.
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Identification of MCM8IP, an interactor of MCM8-9 and RPA1 that promotes homologous recombination and DNA synthesis in response to DNA damage
Jen-Wei Huang, Angelo Taglialatela, Ananya Acharya, Giuseppe Leuzzi, Tarun S. Nambiar, Raquel Cuella-Martin, Samuel B. Hayward, Gregory J. Brunette, Roopesh Anand, Rajesh K. Soni, Nathan L. Clark, Kara A. Bernstein, Petr Cejka, Alberto Ciccia
bioRxiv 751974; doi: https://doi.org/10.1101/751974
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Identification of MCM8IP, an interactor of MCM8-9 and RPA1 that promotes homologous recombination and DNA synthesis in response to DNA damage
Jen-Wei Huang, Angelo Taglialatela, Ananya Acharya, Giuseppe Leuzzi, Tarun S. Nambiar, Raquel Cuella-Martin, Samuel B. Hayward, Gregory J. Brunette, Roopesh Anand, Rajesh K. Soni, Nathan L. Clark, Kara A. Bernstein, Petr Cejka, Alberto Ciccia
bioRxiv 751974; doi: https://doi.org/10.1101/751974

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