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A meiosis-specific BRCA2 binding protein recruits recombinases to DNA double-strand breaks to ensure homologous recombination
Nature Communications ( IF 14.7 ) Pub Date : 2019-02-13 , DOI: 10.1038/s41467-019-08676-2
Jingjing Zhang , Yasuhiro Fujiwara , Shohei Yamamoto , Hiroki Shibuya

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.



中文翻译:

减数分裂特异性BRCA2结合蛋白募集重组酶至DNA双链断裂,以确保同源重组

同源重组(HR)修复DNA双链断裂(DSB),以维持基因组完整性。通过介体蛋白BRCA2募集到DSB的重组酶催化同源性指导的修复。在减数分裂HR期间,已编程的DSB在全基因组范围内引入,但它们的修复机制(包括BRCA2的调控)仍然难以捉摸。在这里,我们确定了BRCA2的减数分裂定位基因MEILB2 / HSF2BP,它定位于小鼠减数分裂DSBs的位点。Meilb2的破坏消除了RAD51和DMC1重组酶在精母细胞中的定位,从而导致了DSB修复和雄性不育的错误。MEILB2直接与BRCA2结合并调节其与减数分裂DSB的关联。我们将BRCA2中的MEILB2结合结构域作图,这与规范的DNA结合结构域不同,但足以以MEILB2依赖性的方式定位于减数分裂DSB。我们得出的结论是,BRCA2定位于减数分裂DSB是由MEILB2介导的,MEILB2是修复大量减数分裂DSB的必要机制。

更新日期:2019-02-14
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