Abstract:
Maintenance of genome stability is of paramount importance for the survival of an organism. However, genomic integrity is constantly being challenged by various endogenous and exogenous processes that damage DNA. Therefore, cells are heavily reliant on DNA repair pathways that have evolved to deal with every type of genotoxic insult that threatens to compromise genome stability. Notably, inherited mutations in genes encoding proteins involved in these protective pathways trigger the onset of disease that is driven by chromosome instability e.g. neurodevelopmental abnormalities, neurodegeneration, premature ageing, immunodeficiency and cancer development. The ability of cells to regulate the recruitment of specific DNA repair proteins to sites of DNA damage is extremely complex but is primarily mediated by protein post-translational modifications (PTMs). Ubiquitylation is one such PTM, which controls genome stability by regulating protein localisation, protein turnover, protein-protein interactions and intra-cellular signalling. Over the past two decades, numerous ubiquitin (Ub) E3 ligases have been identified to play a crucial role not only in the initiation of DNA replication and DNA damage repair but also in the efficient termination of these processes. In this review, we discuss our current understanding of how different Ub E3 ligases (RNF168, TRAIP, HUWE1, TRIP12, FANCL, BRCA1, RFWD3) function to regulate DNA repair and replication and the pathological consequences arising from inheriting deleterious mutations that compromise the Ub-dependent DNA damage response.
摘要:
基因组稳定性的维持对于生物体的生存至关重要。然而,基因组完整性不断受到各种损伤DNA的内源性和外源性过程的挑战。因此,细胞严重依赖DNA修复途径,这些途径已经进化来处理威胁到基因组稳定性的各种基因毒性损伤。值得注意的是,遗传突变的基因编码的蛋白质参与这些保护途径触发疾病的发作是由染色体不稳定,如神经发育异常,神经变性,过早老化,免疫缺陷和癌症发展。细胞调节特定DNA修复蛋白向DNA损伤位点募集的能力极其复杂,但主要由蛋白质翻译后修饰(PTM)介导。泛素化是这样一种PTM,通过调节蛋白质定位来控制基因组的稳定性,蛋白质周转,蛋白质-蛋白质相互作用和细胞内信号传导。在过去的二十年里,已确定许多泛素(Ub)E3连接酶不仅在DNA复制的启动和DNA损伤修复中起关键作用,而且在这些过程的有效终止中起关键作用。在这次审查中,我们讨论了我们目前对不同的UBE3连接酶(RNF168,TRAIP,HUWE1,TRIP12,FANCL,BRCA1,RFWD3)的功能是调节DNA修复和复制以及遗传有害突变引起的病理后果,这些突变损害了Ub依赖性DNA损伤反应。