Homologous recombination (HR) is a crucial pathway for the repair of DNA double-strand breaks. BRCA1/2 breast cancer proteins are key players in HR via their mediation of RAD51 nucleofilament formation and function; however, their individual roles and crosstalk in vivo are unknown. Here we use super-resolution (SR) imaging to map the spatiotemporal kinetics of HR proteins, revealing the interdependent relationships that govern the dynamic interplay and progression of repair events. We show that initial single-stranded DNA/RAD51 nucleofilament formation is mediated by RAD52 or, in the absence of RAD52, by BRCA2. In contrast, only BRCA2 can orchestrate later RAD51 recombinase activity during homology search and resolution. Furthermore, we establish that upstream BRCA1 activity is critical for BRCA2 function. Our analyses reveal the underlying epistatic landscape of RAD51 functional dependence on RAD52, BRCA1, and BRCA2 during HR and explain the phenotypic similarity of diseases associated with mutations in these proteins.

中文翻译：

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在单个折叠的复制叉处同源重组修复的时空动力学。

同源重组（HR）是修复DNA双链断裂的关键途径。BRCA1 / 2乳腺癌蛋白通过调节RAD51核丝的形成和功能而成为HR的关键参与者。然而，它们各自的作用和体内的串扰是未知的。在这里，我们使用超分辨率（SR）成像来绘制HR蛋白的时空动力学图，揭示了控制动态相互作用和修复事件进展的相互依存关系。我们显示，最初的单链DNA / RAD51核丝形成是由RAD52介导的，或者在不存在RAD52的情况下，由BRCA2介导。相反，在同源性搜索和解析过程中，只有BRCA2可以协调后来的RAD51重组酶活性。此外，我们确定上游BRCA1活动对于BRCA2功能至关重要。