Molecular Basis for K63-Linked Ubiquitination Processes in Double-Strand DNA Break Repair: A Focus on Kinetics and Dynamics.
Molecular Basis for K63-Linked Ubiquitination Processes in Double-Strand DNA Break Repair: A Focus on Kinetics and Dynamics.
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DOI：
10.1016/j.jmb.2017.05.029
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发表时间：
2017-11-10
影响因子：
5.6
通讯作者：
Spyracopoulos L
中科院分区：
文献类型：
--
作者：
Lee BL;Singh A;Mark Glover JN;Hendzel MJ;Spyracopoulos L
细胞每天都暴露在成千上万的DNA损伤事件中。这种损伤必须修复，以保存遗传信息，防止疾病的发展。最有害的损伤是双链断裂（DSB），它被称为非同源末端连接（NHEJ）和同源重组（HR）的机制检测和修复，这是DNA损伤反应系统的组成部分。NHEJ是一个容易出错的第一道防线，而HR则调用无错误修复，这是本文的重点。hr驱动DNA修复的蛋白质组分的功能受到翻译后修饰的协调作用，包括赖氨酸乙酰化、磷酸化、泛素化和sumo化。后两种机制是识别dsb和重组染色质以促进修复的基础。我们重点研究了k63连接的泛素链的合成、识别和切割的蛋白质成分的结构和分子机制，这些蛋白质在损伤位点大量存在，并且是DSB修复所必需的。k63连接的泛素化级联的正向通量是由E1酶、异二聚体E2 Mms2-Ubc13及其同源E3连接酶RNF8/RNF168的联合活性驱动的，通过去泛素酶BRCC36和蛋白酶体结合和切割链以及修复蛋白（如RAP80）上的识别模块结合链来平衡。我们强调了我们目前对动力学和动力学在确定驱动k63泛素化的酶和链识别模块的功能方面的作用的理解的一些方面。
Cells are exposed to thousands of DNA damage events on a daily basis. This damage must be repaired to preserve genetic information, and prevent development of disease. The most deleterious damage is a double strand break (DSB), which is detected and repaired by mechanisms known as non-homologous end joining (NHEJ), and homologous recombination (HR), components of the DNA damage response system. NHEJ is an error prone first line of defense, whereas HR invokes error free repair, and is the focus of this review. The functions of the protein components of HR-driven DNA repair are regulated by the coordinated action of post-translational modifications including lysine acetylation, phosphorylation, ubiquitination, and SUMOylation. The latter two mechanisms are fundamental for recognition of DSBs, and reorganizing chromatin to facilitate repair. We focus on the structures and molecular mechanisms for the protein components underlying synthesis, recognition, and cleavage of K63-linked ubiquitin chains, which are abundant at damage sites, and obligatory for DSB repair. The forward flux of the K63-linked ubiquitination cascade is driven by the combined activity of E1 enzyme, the heterodimeric E2 Mms2-Ubc13, and its cognate E3 ligases RNF8/RNF168, which is balanced through the binding and cleavage of chains by the deubiquitinase BRCC36 and the proteasome, as well as binding of chains by recognition modules on repair proteins such as RAP80. We highlight a number of aspects regarding our current understanding for the role of kinetics and dynamics in determining the function of the enzymes and chain recognition modules that drive K63-ubiquitination.
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