Nucleosome acidic patch promotes RNF168- and RING1B/BMI1-dependent H2AX and H2A ubiquitination and DNA damage signaling.
Nucleosome acidic patch promotes RNF168- and RING1B/BMI1-dependent H2AX and H2A ubiquitination and DNA damage signaling.
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核小体酸性贴片促进RNF168-和RING1B/BMI1依赖性H2AX以及H2A泛素化和DNA损伤信号传导。
DOI：
10.1371/journal.pgen.1004178
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发表时间：
2014-03
期刊：
影响因子：
4.5
通讯作者：
Miller KM
中科院分区：
文献类型：
--
作者：
Leung JW;Agarwal P;Canny MD;Gong F;Robison AD;Finkelstein IJ;Durocher D;Miller KM
组蛋白泛素化对于DNA损伤反应（DDR）的激活至关重要。特别地，RNF 168和RING 1B/BMI 1分别通过泛素化Lys-13/15和Lys-118/119上的H2 A/H2 AX在DDR中起作用。然而，泛素途径如何与染色质结合以提供特定组蛋白残基的泛素靶向调节仍有待确定。在这里，我们确定了核小体酸补丁作为一个关键的染色质介质的H2 A/H2 AX泛素化（ub）。在体内，RNF 168和RING 1B/BMI 1依赖性H2 A/H2 AXub需要酸性贴片。酸性补丁在核小体中的功能是含有突变的酸性补丁的核小体在体外通过RNF 168和RING 1B/BMI 1表现出缺陷的H2 A/H2 AXub。此外，通过表达工程化的酸性补丁相互作用病毒肽拉娜在体内直接扰动核小体酸性补丁，导致缺陷的H2 AXub和RNF 168依赖性DNA损伤应答，包括53 BP 1和BRCA 1募集至DNA损伤。因此，酸性补丁是一个关键的核小体特征，可以作为一个支架，以整合染色质上的多种泛素信号，组成选择性的组蛋白上的泛素化DNA损伤信号。组蛋白的翻译后修饰在调节染色质的结构和功能中起着重要作用。由于所有基于DNA的过程，包括转录、DNA复制和DNA修复，都发生在染色质的背景下，这些反应的实际体内底物是染色质。因此，在染色质的背景下理解这些过程对于提供对基于染色质的过程的机械见解是至关重要的，包括DNA损伤信号传导和基因组维护。在这里，我们确定了H2 A和H2 AX中的一个结构，称为酸性补丁，它促进了两个独立的泛素E3连接酶复合物RNF 168和RING 1B/BMI 1的活性，并且是DNA损伤泛素信号传导所必需的。我们直接在体外和体内表明，这种核小体结构是至关重要的组蛋白H2 A和H2 AX泛素化和细胞中的DNA损伤反应。此外，我们设计了一种新的生物工具，它阻断了所有组蛋白H2 A种类的核小体酸性补丁，从而抑制了细胞中的DNA损伤反应。总的来说，DNA损伤因子不仅通过组蛋白修饰如泛素，而且通过核小体表面结构内的相互作用来激活DNA损伤信号传导来引起它们的反应。
Histone ubiquitinations are critical for the activation of the DNA damage response (DDR). In particular, RNF168 and RING1B/BMI1 function in the DDR by ubiquitinating H2A/H2AX on Lys-13/15 and Lys-118/119, respectively. However, it remains to be defined how the ubiquitin pathway engages chromatin to provide regulation of ubiquitin targeting of specific histone residues. Here we identify the nucleosome acid patch as a critical chromatin mediator of H2A/H2AX ubiquitination (ub). The acidic patch is required for RNF168- and RING1B/BMI1-dependent H2A/H2AXub in vivo. The acidic patch functions within the nucleosome as nucleosomes containing a mutated acidic patch exhibit defective H2A/H2AXub by RNF168 and RING1B/BMI1 in vitro. Furthermore, direct perturbation of the nucleosome acidic patch in vivo by the expression of an engineered acidic patch interacting viral peptide, LANA, results in defective H2AXub and RNF168-dependent DNA damage responses including 53BP1 and BRCA1 recruitment to DNA damage. The acidic patch therefore is a critical nucleosome feature that may serve as a scaffold to integrate multiple ubiquitin signals on chromatin to compose selective ubiquitinations on histones for DNA damage signaling. Post-translational modifications of histones play important roles in regulating both the structure and function of chromatin. As all DNA based processes, including transcription, DNA replication and DNA repair, occur within the context of chromatin, the actual in vivo substrate of these reactions is chromatin. Thus, understanding these processes within the context of chromatin is vital for providing mechanistic insights into chromatin-based processes, including DNA damage signaling and genome maintenance. Here we identify a structure within H2A and H2AX termed the acidic patch that promotes the activity of two independent ubiquitin E3 ligase complexes, RNF168 and RING1B/BMI1, and is required for DNA damage ubiquitin signaling. We show directly in vitro and in vivo that this nucleosome structure is critical for histone H2A and H2AX ubiquitinations and the DNA damage response in cells. In addition, we engineered a novel biological tool that blocked the nucleosome acidic patch of all histone H2A species leading to the repression of the DNA damage response in cells. Collectively, DNA damage factors elicit their response not only through histone modifications such as ubiquitin but also through interactions within nucleosome surface structures to activate DNA damage signaling.
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DOI：
10.4161/cc.20919
发表时间：
2012-07-01
期刊：
Cell cycle (Georgetown, Tex.)
影响因子：
--
作者：
Gatti M;Pinato S;Maspero E;Soffientini P;Polo S;Penengo L
通讯作者：
Penengo L
影响因子：
9.2
作者：
Fang, J;Feng, Q;Zhang, Y
通讯作者：
Zhang, Y
影响因子：
64.5
作者：
Gudjonsson, Thorkell;Altmeyer, Matthias;Lukas, Claudia
通讯作者：
Lukas, Claudia
由 53BP1-RIF1 和 BRCA1-CtIP 组成的细胞周期依赖性调节回路控制 DNA 修复途径的选择。
影响因子：
16
作者：
Escribano-Diaz, Cristina;Orthwein, Alexandre;Durocher, Daniel
通讯作者：
Durocher, Daniel
DOI：
10.1126/science.1230624
发表时间：
2013-02-08
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Di Virgilio M;Callen E;Yamane A;Zhang W;Jankovic M;Gitlin AD;Feldhahn N;Resch W;Oliveira TY;Chait BT;Nussenzweig A;Casellas R;Robbiani DF;Nussenzweig MC
通讯作者：
Nussenzweig MC