Structural insight into BRCA1-BARD1 complex recruitment to damaged chromatin
Structural insight into BRCA1-BARD1 complex recruitment to damaged chromatin
复制标题
深入了解 BRCA1-BARD1 复合物招募至受损染色质的结构。
DOI：
10.1016/j.molcel.2021.05.010
复制
发表时间：
2021-07-01
期刊：
影响因子：
16
通讯作者：
Zhou, Zheng
中科院分区：
文献类型：
--
作者：
Dai, Linchang;Dai, Yaxin;Zhou, Zheng
BRCA 1-BARD 1复合物在S-G2阶段指导DNA双链断裂（DSB）修复途径选择无错误同源重组（HR）。将BRCA 1-BARD 1靶向到DSB近端位点需要BARD 1介导的核小体相互作用和组蛋白标记识别。在这里，我们报告的cryo-EM结构的BARD 1结合到一个泛素化的核小体核心颗粒（NCPUb）在3.1埃的分辨率，并说明BARD 1如何同时识别DNA损伤诱导的标记H2 AK 15 ub和DNA复制相关的标记H4 K20 me 0的核小体。体外和体内分析表明，BARD 1-NCPUb复合物通过BARD 1-核小体相互作用、BARD 1-泛素相互作用和BARD 1 ARD结构域-BARD 1 BRCT结构域相互作用而稳定，消除这些相互作用对HR活性是有害的。我们进一步确定了多种致病BARD 1突变，破坏BARD 1-NCPUb相互作用，从而损害HR。总之，这项研究阐明了BRCA 1-BARD 1复合物招募和保留的机制，通过DSB侧翼核小体，并揭示了癌症治疗途径的重要意义。
The BRCA1-BARD1 complex directs the DNA double-strand break (DSB) repair pathway choice to error-free homologous recombination (HR) during the S-G2 stages. Targeting BRCA1-BARD1 to DSB-proximal sites requires BARD1-mediated nucleosome interaction and histone mark recognition. Here, we report the cryo-EM structure of BARD1 bound to a ubiquitinated nucleosome core particle (NCPUb) at 3.1 angstrom resolution and illustrate how BARD1 simultaneously recognizes the DNA damage-induced mark H2AK15ub and DNA replication associated mark H4K20me0 on the nucleosome. In vitro and in vivo analyses reveal that the BARD1-NCPUb complex is stabilized by BARD1-nucleosome interaction, BARD1-ubiquitin interaction, and BARD1 ARD domain-BARD1 BRCT domain interaction, and abrogating these interactions is detrimental to HR activity. We further identify multiple disease-causing BARD1 mutations that disrupt BARD1-NCPUb interactions and hence impair HR. Together, this study elucidates the mechanism of BRCA1-BARD1 complex recruitment and retention by DSB-flanking nucleosomes and sheds important light on cancer therapeutic avenues.