Control of homologous recombination by the HROB-MCM8-MCM9 pathway
Control of homologous recombination by the HROB-MCM8-MCM9 pathway
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DOI：
10.1101/gad.329508.119
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发表时间：
2019-10-01
影响因子：
10.5
通讯作者：
Durocher, Daniel
中科院分区：
文献类型：
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作者：
Hustedt, Nicole;Saito, Yuichiro;Durocher, Daniel
通过同源重组 (HR) 进行 DNA 修复对于基因组完整性、肿瘤抑制和配子形成至关重要。 HR 利用 DNA 合成来修复 DNA 双链断裂和 DNA 复制叉停滞等损伤，但尽管我们对导致同源搜索和链入侵的步骤有了很好的了解，但我们对建立重组相关 DNA 聚合的机制知之甚少。在此，我们报道 C17orf53/HROB 是一种参与 HR 的 OB 折叠因子，通过将 MCM8-MCM9 解旋酶招募到 DNA 损伤位点来促进 DNA 合成。 Hrob 发生靶向突变的小鼠由于生殖细胞耗尽而无法生育，并表现出与 I 减数分裂停滞一致的表型。 HROB-MCM8-MCM9 途径与 HELQ 解旋酶冗余作用，同时缺乏 HROB 和 HELQ 的细胞会严重损害 HR，这表明它们支持 RAD51 下游完成 HR 的两条主要途径。 HROB 在 HR 中的功能让人想起 gp59，后者在噬菌体 T4 重组依赖性 DNA 复制过程中充当复制解旋酶装载者。因此，我们认为 HROB 加载 MCM8-MCM9 可能同样是建立哺乳动物重组相关 DNA 合成的关键步骤。
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.