BRCA1 promotes error-free, homologous recombination-mediated repair (HRR) of DNA double-stranded breaks (DSBs). When excessive and uncontrolled, BRCA1 HRR activity promotes illegitimate recombination and genome disorder. We and others have observed that the BRCA1-associated protein RAP80 recruits BRCA1 to postdamage nuclear foci, and these chromatin structures then restrict the amplitude of BRCA1-driven HRR. What remains unclear is how this process is regulated. Here we report that both BRCA1 poly-ADP ribosylation (PARsylation) and the presence of BRCA1-bound RAP80 are critical for the normal interaction of BRCA1 with some of its partners (e.g., CtIP and BACH1) that are also known components of the aforementioned focal structures. Surprisingly, the simultaneous loss of RAP80 and failure therein of BRCA1 PARsylation results in the dysregulated accumulation in these foci of BRCA1 complexes. This in turn is associated with the intracellular development of a state of hyper-recombination and gross chromosomal disorder. Thus, physiological RAP80-BRCA1 complex formation and BRCA1 PARsylation contribute to the kinetics by which BRCA1 HRR-sustaining complexes normally concentrate in nuclear foci. These events likely contribute to aneuploidy suppression.

中文翻译：

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RAP80和BRCA1 PARsylation可通过防止BRCA1-B / C复合体保留在DNA修复灶中来保护染色体完整性。

BRCA1促进DNA双链断裂（DSB）的无错，同源重组介导的修复（HRR）。当过量且不受控制时，BRCA1 HRR活性会促进非法重组和基因组异常。我们和其他人已经观察到，BRCA1相关蛋白RAP80募集BRCA1来损伤核灶，然后这些染色质结构限制了BRCA1驱动的HRR的幅度。尚不清楚的是如何调节这一过程。在这里，我们报告BRCA1聚ADP核糖基化（PARsylation）和BRCA1结合的RAP80的存在对于BRCA1及其某些伙伴（例如CtIP和BACH1）的正常相互作用至关重要，这些也是上述聚焦蛋白的已知成分。结构。出奇，RAP80的同时丢失和BRCA1 PARsylation的失败会导致BRCA1复合物这些灶中积累的失调。反过来，这又与细胞内过度重组和严重染色体疾病的发展有关。因此，生理学RAP80-BRCA1复合物的形成和BRCA1 PARsylation有助于动力学，BRCA1 HRR维持复合物通常集中在核灶中。这些事件可能有助于非整倍性抑制。