Department of Microbiology and Immunology, University of Saskatchewan, Saskatoon, SK, Canada S7N 5E5.
Beijing Key Laboratory of DNA Damage Responses and College of Life Sciences, Capital Normal University, Beijing, China 100048.
Biochem J. 2020 Jul 31;477(14):2655-2677. doi: 10.1042/BCJ20190579.
DNA-damage tolerance (DDT) is employed by eukaryotic cells to bypass replication-blocking lesions induced by DNA-damaging agents. In budding yeast Saccharomyces cerevisiae, DDT is mediated by RAD6 epistatic group genes and the central event for DDT is sequential ubiquitination of proliferating cell nuclear antigen (PCNA), a DNA clamp required for replication and DNA repair. DDT consists of two parallel pathways: error-prone DDT is mediated by PCNA monoubiquitination, which recruits translesion synthesis DNA polymerases to bypass lesions with decreased fidelity; and error-free DDT is mediated by K63-linked polyubiquitination of PCNA at the same residue of monoubiquitination, which facilitates homologous recombination-mediated template switch. Interestingly, the same PCNA residue is also subjected to sumoylation, which leads to inhibition of unwanted recombination at replication forks. All three types of PCNA posttranslational modifications require dedicated conjugating and ligation enzymes, and these enzymes are highly conserved in eukaryotes, from yeast to human.
DNA 损伤容忍（DDT）是真核细胞用来绕过由 DNA 损伤剂诱导的复制阻断损伤的一种机制。在芽殖酵母酿酒酵母中，DDT 由 RAD6 上位群基因介导，DDT 的核心事件是增殖细胞核抗原（PCNA）的顺序泛素化，PCNA 是复制和 DNA 修复所必需的 DNA 夹。DDT 由两条平行途径组成：易错 DDT 由 PCNA 单泛素化介导，它招募跨损伤合成 DNA 聚合酶以降低保真度绕过损伤；无错 DDT 由 PCNA 同一单泛素化残基上的 K63 连接多泛素化介导，促进同源重组介导的模板转换。有趣的是，同一 PCNA 残基还受到 SUMO 化的修饰，这导致复制叉处不需要的重组的抑制。所有三种类型的 PCNA 翻译后修饰都需要专门的连接酶和连接酶，这些酶在从酵母到人等真核生物中高度保守。
