MCM8IP activates the MCM8-9 helicase to promote DNA synthesis and homologous recombination upon DNA damage
Year: 2020
Type: article
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.
Source: Nature Communications
Language: English
Topic: DNA Repair Mechanisms
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,380
Funders: National Science Foundation, U.S. Department of Health and Human Services, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Associazione Italiana per la Ricerca sul Cancro, National Institutes of Health, Stand Up To Cancer, National Human Genome Research Institute, National Cancer Institute, National Institute of Environmental Health Sciences, H2020 European Research Council
Awards: Replication fork dynamics and repair by Rad51 paralogues after DNA alkylation, Beyond DNA end resection: Role of homologous recombination in the maintenance of genome stability, G1810648499, Theory-driven Situational Design of Enterprise Information Systems, Restoring genome stability and tumor suppression in BRCA1 deficient cells, Nucleases in homologous recombination: from basic principles to genome editing, G7654714045, Cancer Biology Training Grant, G9000090167, Replication fork dynamics and repair by Rad51 paralogs after DNA alkylation, Title: Functional Annotation of Genomes via Phenotypic Convergence within Large Multi-species Alignments, Regulation of DNA synthesis in response to DNA damage, Cancer Center Support Grant
OpenAlex ID: W3034945988