期刊
ENVIRONMENTAL AND MOLECULAR MUTAGENESIS
卷 61, 期 7, 页码 680-692出版社
WILEY
DOI: 10.1002/em.22359
关键词
DNA damage tolerance; translesion DNA synthesis; TLS polymerase; chemotherapy
资金
- National Key R&D Program of China [2018YFA0108500]
- CAS Strategic Priority Research Program [XDA16010107]
- National Natural Science Foundation of China [81630078, 91754204, 31970740, 31800684, 31670822]
- Natural Science Foundation of Beijing [5181001]
- Natural Science Foundation of Shanxi Province [201801D221281]
- State Key Laboratory of Membrane Biology
- Key Laboratory of Genomic and Precision Medicine of the CAS
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. 2020. (c) 2020 Wiley Periodicals, Inc.
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