Department of Chemistry and Molecular Biology, University of Gothenburg, SE-40530, Gothenburg, Sweden.
Institute for Quantitative Biosciences, University of Tokyo, 1-1-1 Yayoi, Tokyo, 113-0032, Japan.
Nat Commun. 2019 Feb 13;10(1):722. doi: 10.1038/s41467-019-08676-2.
Homologous recombination (HR) repairs DNA double-strand breaks (DSBs) to maintain genomic integrity. Recombinase recruited to the DSBs by the mediator protein BRCA2 catalyzes the homology-directed repair. During meiotic HR, programmed DSBs are introduced genome-wide but their repair mechanisms, including the regulation of BRCA2, have remained largely elusive. Here we identify a meiotic localizer of BRCA2, MEILB2/HSF2BP, that localizes to the site of meiotic DSBs in mice. Disruption of Meilb2 abolishes the localization of RAD51 and DMC1 recombinases in spermatocytes, leading to errors in DSB repair and male sterility. MEILB2 directly binds to BRCA2 and regulates its association to meiotic DSBs. We map the MEILB2-binding domain within BRCA2 that is distinct from the canonical DNA-binding domain but is sufficient to localize to meiotic DSBs in a MEILB2-dependent manner. We conclude that localization of BRCA2 to meiotic DSBs is mediated by MEILB2, which is an integral mechanism to repair abundant meiotic DSBs.
同源重组 (HR) 修复 DNA 双链断裂 (DSBs) 以维持基因组完整性。由中介蛋白 BRCA2 募集到 DSB 的重组酶催化同源定向修复。在减数分裂 HR 中，程序性 DSB 被广泛引入基因组，但它们的修复机制，包括 BRCA2 的调控，在很大程度上仍然难以捉摸。在这里，我们鉴定了 BRCA2 的一种减数分裂定位因子 MEILB2/HSF2BP，它在小鼠中定位于减数分裂 DSB 位点。Meilb2 的破坏导致 RAD51 和 DMC1 重组酶在精母细胞中的定位缺失，导致 DSB 修复错误和雄性不育。MEILB2 直接与 BRCA2 结合，并调节其与减数分裂 DSB 的结合。我们在 BRCA2 内定位 MEILB2 结合域，该域与经典 DNA 结合域不同，但足以以 MEILB2 依赖的方式定位于减数分裂 DSB。我们得出结论，BRCA2 到减数分裂 DSB 的定位是由 MEILB2 介导的，这是修复大量减数分裂 DSB 的一个整体机制。
