Control of homologous recombination by the HROB-MCM8-MCM9 pathway

• Published in: Genes & development Vol. 33; no. 19-20; pp. 1397 - 1415
• Main Authors: Hustedt, Nicole, Saito, Yuichiro, Zimmermann, Michal, Álvarez-Quilón, Alejandro, Setiaputra, Dheva, Adam, Salomé, McEwan, Andrea, Yuan, Jing Yi, Olivieri, Michele, Zhao, Yichao, Kanemaki, Masato T, Jurisicova, Andrea, Durocher, Daniel
• Format: Journal Article
• Language: English
• Published: United States Cold Spring Harbor Laboratory Press 01.10.2019
• Subjects: Animals; Cell Line; DNA Helicases - metabolism; DNA Repair - genetics; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Female; HCT116 Cells; HEK293 Cells; HeLa Cells; Homologous Recombination - genetics; Humans; Infertility - genetics; Male; Mice, Inbred C57BL; Minichromosome Maintenance Proteins - metabolism; Research Paper; Sequence Deletion; Sf9 Cells; homologous recombination; DNA damage; DNA synthesis; CRISPR screens; helicase; cisplatin; infertility; DNA repair; germ cells
• ISSN: 0890-9369; 1549-5477
• DOI: 10.1101/gad.329508.119

DNA repair by homologous recombination (HR) is essential for genomic integrity, tumor suppression, and the formation of gametes. HR uses DNA synthesis to repair lesions such as DNA double-strand breaks and stalled DNA replication forks, but despite having a good understanding of the steps leading to homology search and strand invasion, we know much less of the mechanisms that establish recombination-associated DNA polymerization. Here, we report that C17orf53/HROB is an OB-fold-containing factor involved in HR that acts by recruiting the MCM8-MCM9 helicase to sites of DNA damage to promote DNA synthesis. Mice with targeted mutations in are infertile due to depletion of germ cells and display phenotypes consistent with a prophase I meiotic arrest. The HROB-MCM8-MCM9 pathway acts redundantly with the HELQ helicase, and cells lacking both HROB and HELQ have severely impaired HR, suggesting that they underpin two major routes for the completion of HR downstream from RAD51. The function of HROB in HR is reminiscent of that of gp59, which acts as the replicative helicase loader during bacteriophage T4 recombination-dependent DNA replication. We therefore propose that the loading of MCM8-MCM9 by HROB may similarly be a key step in the establishment of mammalian recombination-associated DNA synthesis.