Maintaining stability of the genome requires dedicated DNA repair and signalling processes that are essential for the faithful duplication and propagation of chromosomes. These DNA damage response (DDR) mechanisms counteract the potentially mutagenic impact of daily genotoxic stresses from both exogenous and endogenous sources. Inherent to these DNA repair pathways is the activity of protein factors that instigate repair processes in response to DNA lesions. The regulation, coordination, and orchestration of these DDR factors is carried out, in a large part, by post-translational modifications, such as phosphorylation, ubiquitylation, and modification with ubiquitin-like proteins (UBLs). The importance of ubiquitylation and UBLylation with SUMO in DNA repair is well established, with the modified targets and downstream signalling consequences relatively well characterised. However, the role of dedicated erasers for ubiquitin and UBLs, known as deubiquitylases (DUBs) and ubiquitin-like proteases (ULPs) respectively, in genome stability is less well established, particularly for emerging UBLs such as ISG15 and UFM1. In this review, we provide an overview of the known regulatory roles and mechanisms of DUBs and ULPs involved in genome stability pathways. Expanding our understanding of the molecular agents and mechanisms underlying the removal of ubiquitin and UBL modifications will be fundamental for progressing our knowledge of the DDR and likely provide new therapeutic avenues for relevant human diseases, such as cancer.

中文翻译：

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倍增：泛素和泛素样蛋白酶在基因组稳定性中的作用


维持基因组的稳定性需要专门的 DNA 修复和信号传导过程，这对于染色体的忠实复制和传播至关重要。这些 DNA 损伤反应 (DDR) 机制抵消了来自外源和内源的日常基因毒性应激的潜在致突变影响。这些 DNA 修复途径固有的是蛋白质因子的活性，这些蛋白质因子可响应 DNA 损伤而启动修复过程。这些 DDR 因子的调节、协调和编排在很大程度上是通过翻译后修饰来实现的，例如磷酸化、泛素化和泛素样蛋白 (UBL) 修饰。 SUMO 泛素化和 UBLy 化在 DNA 修复中的重要性已得到充分证实，修饰的靶标和下游信号转导结果也相对较好地表征。然而，泛素和 UBL 的专用擦除器（分别称为去泛素酶 (DUB) 和泛素样蛋白酶 (ULP)）在基因组稳定性中的作用尚不清楚，特别是对于 ISG15 和 UFM1 等新兴 UBL 而言。在这篇综述中，我们概述了参与基因组稳定性途径的 DUB 和 ULP 的已知调控作用和机制。扩大我们对消除泛素和 UBL 修饰的分子制剂和机制的理解对于增进我们对 DDR 的了解至关重要，并可能为癌症等相关人类疾病提供新的治疗途径。