Control of homologous recombination by the HROB–MCM8–MCM9 pathway
Nicole Hustedt, Yuichiro Saito, Michal Zimmermann, Alejandro Álvarez-Quilón, Dheva Setiaputra, Salomé Adam, Andrea McEwan, Jing Yi Yuan, Michele Olivieri, Yichao Zhao, Masato T. Kanemaki, Andrea Jurisicova, and Daniel Durocher
Genes & Development online advanced publication DOI:10.1101/gad.329508.119
Most organisms including humans have two copies of genomic DNA, each of which is originated from the parents. Homologous Recombination (HR) is a reaction, which copy the sequence of donor DNA and paste it to the recipient DNA. HR plays a critical role in meiosis for gametogenesis and in damaged DNA repair during DNA replication or after irradiation, the latter of which is important to prevent cell death and cancer formation.
HR searches the donor sequence and synthesize DNA to copy and paste it to the recipient ones. Despite having a good understanding of the protein roles in the earlier steps in HR, much less is known about HR-associated DNA synthesis. We have studied MCM8–9, which is essential for HR-associated DNA synthesis. As a collaboration with the group led by Prof. Daniel Durocher at University of Toronto, we identified a new factor, HROB, which has an important role for loading MCM8–9 at the damaged DNA sites. Similar to the phenotypes of MCM8–9 loss, human cells lacking HROB showed a strong defect in DNA repair during DNA replication and HROB knockout mice were sterile, showing that, together with MCM8–9, HROB is important for genome maintenance and meiosis. We expect that elucidating HR, in which HROB and MCM8–9 are involved, would help cancer and fertility treatments in the future.
Figure: HR searches the donor sequence and uses DNA synthesis to copy and paste it to the recipient ones. In this paper, we found a novel factor, HROB, which promotes MCM8–9 loading to promote HR-associated DNA synthesis.