The genomes of all living cells are under endogenous and exogenous attacks every day, causing diverse genomic lesions. Most of the lesions can be timely repaired by multiple DNA repair pathways. However, some may persist during S‐phase, block DNA replication, and challenge genome integrity. Eukaryotic cells have evolved DNA damage tolerance (DDT) to mitigate the lethal effects of arrested DNA replication without prior removal of the offending DNA damage. As one important mode of DDT, translesion DNA synthesis (TLS) utilizes multiple low‐fidelity DNA polymerases to incorporate nucleotides opposite DNA lesions to maintain genome integrity. Three different mechanisms have been proposed to regulate the polymerase switching between high‐fidelity DNA polymerases in the replicative machinery and one or more specialized enzymes. Additionally, it is known that proliferating cell nuclear antigen (PCNA) mono‐ubiquitination is essential for optimal TLS. Given its error‐prone property, TLS is closely associated with spontaneous and drug‐induced mutations in cells, which can potentially lead to tumorigenesis and chemotherapy resistance. Therefore, TLS process must be tightly modulated to avoid unwanted mutagenesis. In this review, we will focus on polymerase switching and PCNA mono‐ubiquitination, the two key events in TLS pathway in mammalian cells, and summarize current understandings of regulation of TLS process at the levels of protein–protein interactions, post‐translational modifications as well as transcription and noncoding RNAs. Environ. Mol. Mutagen. 61:680–692, 2020. © 2020 Wiley Periodicals, Inc.

中文翻译：

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哺乳动物细胞中跨病变DNA合成的调控。

每天，所有活细胞的基因组都受到内源性和外源性攻击，从而导致各种基因组损伤。大多数病变可以通过多种DNA修复途径及时修复。但是，有些可能在S期持续存在，阻断DNA复制并挑战基因组完整性。真核细胞已进化出DNA损伤耐受性（DDT），以减轻被捕的DNA复制的致死作用，而无需事先消除有害的DNA损伤。作为DDT的一种重要模式，跨病变DNA合成（TLS）利用多种低保真DNA聚合酶掺入与DNA病变相对的核苷酸，以保持基因组完整性。已经提出了三种不同的机制来调节复制机制中高保真DNA聚合酶与一种或多种特殊酶之间的聚合酶转换。另外，众所周知，增殖细胞核抗原（PCNA）单泛素化对于最佳TLS是必不可少的。鉴于TLS容易出错的特性，它与细胞中自发的和药物诱导的突变密切相关，这可能导致肿瘤发生和化疗耐药。因此，必须严格调整TLS流程，以避免不必要的诱变。在这篇综述中，我们将重点研究哺乳动物细胞中TLS途径中的两个关键事件聚合酶转换和PCNA单泛素化，并总结当前对TLS过程调控的理解，包括蛋白质间相互作用，翻译后修饰等。以及转录和非编码RNA。环境。大声笑 诱变剂。61：680–692，2020。©2020 Wiley Periodicals，Inc.