美国纽约大学格罗斯曼医学院Eli Rothenberg课题组报道了BRCA2阻止PARPi介导的PARP1保留，以保护RAD51细丝。相关论文发表在2025年3月26日出版的《自然》杂志上。

在这里，小组确定了BRCA2的一个以前未知的作用，它与PARP1抑制的作用直接相关。利用生物化学和单分子方法，课题组研究人员证明了PARPi介导的PARP1在切除的DNA底物上的保留会干扰RAD51丝的稳定性，并损害RAD51介导的DNA链交换。全长BRCA2保护RAD51细丝，并通过阻止PARP1与DNA的结合来抵消PARPi介导的保留所带来的不稳定性。将这些发现扩展到细胞背景下，课题组使用定量单分子定位显微镜来显示BRCA2阻止PARPi诱导的PARP1保留在同源重组修复位点。相比之下，BRCA2缺陷细胞在这些病变处表现出PARP1保留增加以响应PARPi。这些结果为BRCA2在维持RAD51稳定性和通过减轻PARP介导的PARP1保留来保护同源重组修复位点中的作用提供了机制见解。

据了解，肿瘤抑制蛋白BRCA2通过增强双链DNA断裂时产生的切除单链DNA上RAD51细丝的形成和刺激RAD51活性，在同源定向DNA修复中发挥核心作用。携带BRCA2突变的个体易患癌症；然而，BRCA2缺陷肿瘤通常对PARP抑制剂（PARPi）靶向治疗有反应。BRCA2缺乏使细胞对PARPi敏感，但对BRCA2突变的杂合细胞毒性最小的机制尚不清楚。

附：英文原文

Title: BRCA2 prevents PARPi-mediated PARP1 retention to protect RAD51 filaments

Author: Lahiri, Sudipta, Hamilton, George, Moore, Gemma, Goehring, Liana, Huang, Tony T., Jensen, Ryan B., Rothenberg, Eli

Issue&Volume: 2025-03-26

Abstract: The tumour-suppressor protein BRCA2 has a central role in homology-directed DNA repair by enhancing the formation of RAD51 filaments on resected single-stranded DNA generated at double-stranded DNA breaks and stimulating RAD51 activity1,2. Individuals with BRCA2 mutations are predisposed to cancer; however, BRCA2-deficient tumours are often responsive to targeted therapy with PARP inhibitors (PARPi)3,4,5,6. The mechanism by which BRCA2 deficiency renders cells sensitive to PARPi but with minimal toxicity in cells heterozygous for BRCA2 mutations remains unclear. Here we identify a previously unknown role of BRCA2 that is directly linked to the effect of PARP1 inhibition. Using biochemical and single-molecule approaches, we demonstrate that PARPi-mediated PARP1 retention on a resected DNA substrate interferes with RAD51 filament stability and impairs RAD51-mediated DNA strand exchange. Full-length BRCA2 protects RAD51 filaments and counteracts the instability conferred by PARPi-mediated retention by preventing the binding of PARP1 to DNA. Extending these findings to a cellular context, we use quantitative single-molecule localization microscopy to show that BRCA2 prevents PARPi-induced PARP1 retention at homologous-recombination repair sites. By contrast, BRCA2-deficient cells exhibit increased PARP1 retention at these lesions in response to PARPi. These results provide mechanistic insights into the role of BRCA2 in maintaining RAD51 stability and protecting homologous-recombination repair sites by mitigating PARPi-mediated PARP1 retention.

DOI: 10.1038/s41586-025-08749-x

Source: https://www.nature.com/articles/s41586-025-08749-x