RNF168 Promotes Noncanonical K27 Ubiquitination to Signal DNA Damage
RNF168 Promotes Noncanonical K27 Ubiquitination to Signal DNA Damage
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DOI：
10.1016/j.celrep.2014.12.021
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发表时间：
2015-01-13
期刊：
影响因子：
8.8
通讯作者：
Penengo, Lorenza
中科院分区：
文献类型：
--
作者：
Gatti, Marco;Pinato, Sabrina;Penengo, Lorenza
泛素化通过产生基于通过不同残基连接的八个结构和功能不同的链的通用通信系统来调节许多细胞过程。除了K48和K63，不同连接的生物学相关性在很大程度上是不清楚的。在这里，我们表明，RNF 168泛素连接酶促进非经典K27连接的泛素化在体内和体外。我们证明了泛素残基K27（UbK 27）是RNF 168依赖的染色质泛素化所必需的，通过靶向组蛋白H2 A/H2A.X，并且它是DNA损伤后标记染色质的主要基于泛素的修饰。事实上，UbK 27是正确激活DNA损伤反应（DDR）所严格需要的，并且直接被关键的DDR介导物，即53 BP 1，Rap 80，RNF 168和RNF 169识别。UbK 27的突变对DDR激活具有显著影响，阻止了53 BP 1和BRCA 1募集到DDR病灶。与DDR类似，非典型泛素链可能在其他关键的泛素介导的生物过程中发挥意想不到的作用。
Ubiquitination regulates numerous cellular processes by generating a versatile communication system based on eight structurally and functionally different chains linked through distinct residues. Except for K48 and K63, the biological relevance of different linkages is largely unclear. Here, we show that RNF168 ubiquitin ligase promotes noncanonical K27-linked ubiquitination both in vivo and in vitro. We demonstrate that residue K27 of ubiquitin (UbK27) is required for RNF168-dependent chromatin ubiquitination, by targeting histones H2A/H2A.X, and that it is the major ubiquitin-based modification marking chromatin upon DNA damage. Indeed, UbK27 is strictly required for the proper activation of the DNA damage response (DDR) and is directly recognized by crucial DDR mediators, namely 53BP1, Rap80, RNF168, and RNF169. Mutation of UbK27 has dramatic consequences on DDR activation, preventing the recruitment of 53BP1 and BRCA1 to DDR foci. Similarly to the DDR, atypical ubiquitin chains could play unanticipated roles in other crucial ubiquitin-mediated biological processes.