College of Life Sciences, Capital Normal University, Beijing, 100048, China; Department of Microbiology and Immunology, University of Saskatchewan, Saskatoon, SK, Canada.
Department of Microbiology and Immunology, University of Saskatchewan, Saskatoon, SK, Canada.
Mutat Res Rev Mutat Res. 2015 Apr-Jun;764:43-50. doi: 10.1016/j.mrrev.2015.02.001. Epub 2015 Feb 16.
DNA-damage tolerance (DDT) is an important mechanism for living cells to bypass replication blocks on the template strand. In Saccharomyces cerevisiae, DDT is mediated by the RAD6 epistasis group of genes, consisting of two parallel pathways: error-prone translesion DNA synthesis (TLS), and error-free lesion bypass. The two pathways are activated by sequential ubiquitination of PCNA on the Lys164 residue. When a replication fork is stalled at a lesion, PCNA is first monoubiquitinated by Rad6-Rad18, which leads to the TLS pathway. The subsequent ubiquitination by the Mms2-Ubc13-Rad5 complex on the monoubiquitinated PCNA is to form a Lys63-linked polyubiquitin chain that promotes error-free lesion bypass. While the TLS pathway has been extensively characterized, the molecular events leading to error-free lesion bypass by polyubiquitinated PCNA are largely obscure. Furthermore, PCNA can also be sumoylated at the same Lys164 residue, which helps to recruit Srs2, a helicase and anti-recombinase. This review summarizes recent advances in our understanding of error-free DDT and its interplay with Srs2 and homologous recombination.
DNA 损伤容忍（DDT）是生物细胞绕过模板链复制障碍的重要机制。在酿酒酵母中，DDT 由 RAD6 遗传因子组介导，该遗传因子组由两条平行途径组成：易错跨损伤 DNA 合成（TLS）和无差错损伤绕过。这两条途径通过 PCNA 赖氨酸 164 残基上的顺序泛素化激活。当复制叉在损伤处停滞时，PCNA 首先被 Rad6-Rad18 单泛素化，从而激活 TLS 途径。随后，Mms2-Ubc13-Rad5 复合物对单泛素化 PCNA 的泛素化导致形成促进无差错损伤绕过的 Lys63 连接多泛素链。虽然 TLS 途径已得到广泛研究，但多泛素化 PCNA 导致无差错损伤绕过的分子事件在很大程度上仍不清楚。此外，PCNA 还可以在同一赖氨酸 164 残基上被 SUMO 化，这有助于招募解旋酶和抗重组酶 Srs2。本综述总结了我们对无差错 DDT 及其与 Srs2 和同源重组相互作用的理解的最新进展。
