小柯机器人

美国梅奥医学中心Georges Mer团队揭示BRCA1-BARD1核糖体识别和泛素化的机制。相关论文于2021年7月28日在线发表在《自然》杂志上。

研究人员使用冷冻电镜发现，BARD1的ankyrin重复和串联BRCT结构域采用紧凑的折叠，并与核糖体组蛋白、DNA和连接到H2A氨基末端K13或K15的单双链蛋白结合，这两个信号是已知的双链断裂特异性信号。结果进一步表明，BRCA1-BARD1中的RING结构使核糖体上的E2泛素结合酶处于动态构象中，为泛素转移到H2A和变体H2AX的灵活羧基端尾部做好准备。这项工作揭示了一种调节串联，其中BRCA1-BARD1在H2A的N端识别单泛素，阻止了多泛素链的形成，并合作促进H2A的C端泛素化。

这些发现阐明了BRCA1-BARD1染色质招募和泛素化特异性的机制，突出了BARD1在这两个过程中的关键功能，并解释了BRCA1-BARD1如何通过反对复制后染色质中的DNA修复蛋白53BP1促进同源重组。这些数据提供了一个评估BARD1变体的结构框架，并有助于识别驱动癌症发展的突变。

据介绍，BRCA1-BARD1肿瘤抑制因子是一种E3泛素连接酶，是通过同源重组修复DNA双链断裂所必需的。BRCA1-BARD1复合物在DNA复制后定位到受损的染色质上，并催化组蛋白H2A和其他细胞靶标的泛素化。BRCA1-BARD1被招募到双链断裂处和靶标识别的分子基础仍然未知。

附：英文原文

Title: Mechanisms of BRCA1–BARD1 nucleosome recognition and ubiquitylation

Author: Hu, Qi, Botuyan, Maria Victoria, Zhao, Debiao, Cui, Gaofeng, Mer, Elie, Mer, Georges

Issue&Volume: 2021-07-28

Abstract: The BRCA1–BARD1 tumour suppressor is an E3 ubiquitin ligase necessary for the repair of DNA double-strand breaks by homologous recombination1,2,3,4,5,6,7,8,9,10. The BRCA1–BARD1 complex localizes to damaged chromatin after DNA replication and catalyses the ubiquitylation of histone H2A and other cellular targets11,12,13,14. The molecular bases for the recruitment to double-strand breaks and target recognition of BRCA1–BARD1 remain unknown. Here we use cryo-electron microscopy to show that the ankyrin repeat and tandem BRCT domains in BARD1 adopt a compact fold and bind to nucleosomal histones, DNA and monoubiquitin attached to H2A amino-terminal K13 or K15, two signals known to be specific for double-strand breaks15,16. We further show that RING domains17 in BRCA1–BARD1 orient an E2 ubiquitin-conjugating enzyme atop the nucleosome in a dynamic conformation, primed for ubiquitin transfer to the flexible carboxy-terminal tails of H2A and variant H2AX. Our work reveals a regulatory crosstalk in which recognition of monoubiquitin by BRCA1–BARD1 at the N terminus of H2A blocks the formation of polyubiquitin chains and cooperatively promotes ubiquitylation at the C terminus of H2A. These findings elucidate the mechanisms of BRCA1–BARD1 chromatin recruitment and ubiquitylation specificity, highlight key functions of BARD1 in both processes and explain how BRCA1–BARD1 promotes homologous recombination by opposing the DNA repair protein 53BP1 in post-replicative chromatin18,19,20,21,22. These data provide a structural framework to evaluate BARD1 variants and help to identify mutations that drive the development of cancer.

DOI: 10.1038/s41586-021-03716-8

Source: https://www.nature.com/articles/s41586-021-03716-8

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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