Kudriaeva A A, Lipkin V M, Belogurov A A
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia.
Moscow State University, Moscow, Russia.
Dokl Biochem Biophys. 2020 Jul;493(1):193-197. doi: 10.1134/S1607672920040079. Epub 2020 Sep 7.
The cellular response to DNA damage protects the essential information stored in the genome. This mechanism is crucial in terms of the cancer prevention and aging progression. The DNA damage response (DDR) consists of a complex network controlling the cell cycle and multiple mechanisms of the DNA repair. The DDR disruption is a cornerstone feature of the tumor cells, which allows them to enhance beneficial mutations that prevent successful disease treatment. The important checkpoints of the DDR are currently poorly understood due to the complexity and diversity of the DNA repair machinery. Histone ubiquitination is intensively involved in the repair of the double-stranded DNA breaks. This post-translational modification is known to be a key factor in the recruitment of the repair factors to the DNA damage sites. Here, the crucial role of the ubiquitin lysine residue K27 in the process of histone H2A monoubiquitination mediated by the ubiquitin ligase RNF168 has been showed. The presented data suggest forced and intensive diffusion of ubiquitin from the cytoplasm to the nucleus, which is characterized by the dynamic equilibrium less than 10 min. The comparison of the turnover rate of the wild-type ubiquitin and its variant with a single functional lysine residue K27 suggests an important role of the ubiquitin deposition as a covalent conjugate with histone H2A in terms of the stability of the entire ubiquitinome.
细胞对DNA损伤的反应可保护基因组中存储的重要信息。该机制在癌症预防和衰老进程方面至关重要。DNA损伤反应（DDR）由一个控制细胞周期的复杂网络和多种DNA修复机制组成。DDR破坏是肿瘤细胞的一个基本特征，这使得它们能够增加有益突变，从而阻碍疾病的成功治疗。由于DNA修复机制的复杂性和多样性，目前对DDR的重要检查点了解甚少。组蛋白泛素化深入参与双链DNA断裂的修复。已知这种翻译后修饰是将修复因子招募到DNA损伤位点的关键因素。在此，已表明泛素赖氨酸残基K27在泛素连接酶RNF168介导的组蛋白H2A单泛素化过程中起关键作用。所呈现的数据表明泛素从细胞质到细胞核的强制和密集扩散，其特征是动态平衡小于10分钟。野生型泛素及其具有单个功能性赖氨酸残基K27的变体的周转速率比较表明，泛素作为与组蛋白H2A的共价缀合物的沉积在整个泛素组的稳定性方面具有重要作用。
