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.

中文翻译：

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E3 连接酶：DNA 修复、DNA 复制和人类疾病之间普遍存在的联系。


维持基因组稳定性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 的内源和外源过程的挑战。因此，细胞严重依赖 DNA 修复途径，这些途径已经进化到能够应对各种可能损害基因组稳定性的基因毒性损伤。值得注意的是，编码参与这些保护途径的蛋白质的基因的遗传突变会引发由染色体不稳定驱动的疾病的发作，例如神经发育异常、神经变性、过早衰老、免疫缺陷和癌症发展。细胞调节特定 DNA 修复蛋白募集至 DNA 损伤位点的能力极其复杂，但主要由蛋白质翻译后修饰 (PTM) 介导。泛素化就是这样一种 PTM，它通过调节蛋白质定位、蛋白质周转、蛋白质-蛋白质相互作用和细胞内信号传导来控制基因组稳定性。在过去的二十年中，许多泛素 (Ub) E3 连接酶已被确定不仅在 DNA 复制的启动和 DNA 损伤修复中发挥着至关重要的作用，而且在这些过程的有效终止中也发挥着至关重要的作用。在这篇综述中，我们讨论了目前对不同 Ub E3 连接酶（RNF168、TRAIP、HUWE1、TRIP12、FANCL、BRCA1、RFWD3）如何发挥调节 DNA 修复和复制功能的理解，以及因遗传损害 Ub 的有害突变而产生的病理后果。依赖性DNA损伤反应。