Control of homologous recombination by the HROB–MCM8–MCM9 pathway
- Nicole Hustedt1,7,
- Yuichiro Saito2,
- Michal Zimmermann1,8,
- Alejandro Álvarez-Quilón1,
- Dheva Setiaputra1,
- Salomé Adam1,
- Andrea McEwan1,
- Jing Yi Yuan1,
- Michele Olivieri1,3,
- Yichao Zhao1,3,
- Masato T. Kanemaki2,4,
- Andrea Jurisicova1,5,6 and
- Daniel Durocher1,3
- 1Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada;
- 2Department of Chromosome Science, National Institute of Genetics, Mishima, Shizuoka 411-8540, Japan;
- 3Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada;
- 4Department of Genetics, SOKENDAI, Mishima, Shizuoka 411-8540, Japan;
- 5Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada;
- 6Department of Obstetrics and Gynecology, University of Toronto, Toronto, Ontario M5G 0D8, Canada
- Corresponding author: durocher{at}lunenfeld.ca
Abstract
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 Hrob 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.
Keywords
- CRISPR screens
- cisplatin
- DNA damage
- DNA repair
- DNA synthesis
- germ cells
- helicase
- homologous recombination
- infertility
Footnotes
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.329508.119.
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Freely available online through the Genes & Development Open Access option.
- Received June 10, 2019.
- Accepted August 8, 2019.
This article, published in Genes & Development, is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.