Three-Dimensional Architecture of the Human BRCA1-A Histone Deubiquitinase Core Complex.
Three-Dimensional Architecture of the Human BRCA1-A Histone Deubiquitinase Core Complex.
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DOI：
10.1016/j.celrep.2016.11.063
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发表时间：
2016-12-20
期刊：
影响因子：
8.8
通讯作者：
Smerdon SJ
中科院分区：
文献类型：
--
作者：
Kyrieleis OJP;McIntosh PB;Webb SR;Calder LJ;Lloyd J;Patel NA;Martin SR;Robinson CV;Rosenthal PB;Smerdon SJ
BRCA1是一种在遗传性乳腺癌和卵巢癌中发现突变的抑癌基因，通过同源重组修复在维持基因组稳定性中起关键作用。它作为BRCA1-A去泛素酶的一个组成部分被招募到受损的染色质上，该酶可以切割附着在组蛋白H2A和H2AX上的k63连接的泛素链。BRCA1-A通过分子机制参与检查点调节、修复途径选择和HR修复效率，其机制目前仍不清楚。由两个Abraxas/BRCC36/BRCC45/MERIT40四聚体组成的活性核心复合物的结构通过负染色电子显微镜（EM）确定，揭示了扭曲的v型结构，其中Abraxas/BRCC36异二聚体的二聚体位于碱基，BRCC45/MERIT40对占据每个臂。BRCC45的位置和泛素结合活性表明，它可能与核小体连接的泛素链提供辅助相互作用，有助于它们的有效加工。我们的数据还表明，共济失调毛细血管扩张突变（ATM）依赖性BRCA1二聚化可能稳定整个BRCA1- a复合物的自我结合。人类BRCA1-A去泛素酶核心复合体的v形结构可能在细胞质BRISC复合体BRCC45/BRE中保守，有助于lys63连接的泛素链结合。Kyrieleis等人使用负染色电镜、质谱和结合分析来表征BRCA1-A这一主要的brca1相互作用复合体。展示了核心四蛋白组装的整体结构，以及它在双链DNA断裂信号传导中作为组蛋白去泛素酶的作用。
BRCA1 is a tumor suppressor found to be mutated in hereditary breast and ovarian cancer and plays key roles in the maintenance of genomic stability by homologous recombination repair. It is recruited to damaged chromatin as a component of the BRCA1-A deubiquitinase, which cleaves K63-linked ubiquitin chains attached to histone H2A and H2AX. BRCA1-A contributes to checkpoint regulation, repair pathway choice, and HR repair efficiency through molecular mechanisms that remain largely obscure. The structure of an active core complex comprising two Abraxas/BRCC36/BRCC45/MERIT40 tetramers determined by negative-stain electron microscopy (EM) reveals a distorted V-shape architecture in which a dimer of Abraxas/BRCC36 heterodimers sits at the base, with BRCC45/Merit40 pairs occupying each arm. The location and ubiquitin-binding activity of BRCC45 suggest that it may provide accessory interactions with nucleosome-linked ubiquitin chains that contribute to their efficient processing. Our data also suggest how ataxia telangiectasia mutated (ATM)-dependent BRCA1 dimerization may stabilize self-association of the entire BRCA1-A complex. Structure of the core complex of the human BRCA1-A deubiquitinase V-shaped architecture likely conserved in the cytoplasmic BRISC complex BRCC45/BRE contributes to Lys63-linked ubiquitin chain binding Kyrieleis et al. have used negative stain electron microscopy along with mass spectrometry and binding assays to characterize one of the major BRCA1-interacting complexes, BRCA1-A, showing the overall architecture of the core four-protein assembly and how this relates to its role as a histone deubiquitinase in double-stranded DNA break signaling.
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