Involvement of Rev1 in alkylating agent-induced loss of heterozygosity in Oryzias latipes.
Involvement of Rev1 in alkylating agent-induced loss of heterozygosity in Oryzias latipes.
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Rev1 参与烷化剂诱导的 Oryzias latipes 杂合性丧失。
DOI：
10.1111/gtc.12746
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发表时间：
2020
期刊：
影响因子：
2.1
通讯作者：
Todo T
中科院分区：
文献类型：
--
作者：
Fujikawa Y;Ishikawa-Fujiwara T;Kuo T;Shinkai N;Shoji T;Kawasaki T;Kamei Y;Sakuraba Y;Sato A;Kinoshita M;Gondo Y;Yuba S;Tsujimura T;Sese J;Todo T
转录合成（TLS）聚合酶在复制期间介导DNA损伤旁路。TLS聚合酶Rev 1在TLS途径中具有两个重要功能，包括dCMP转移酶活性和在C末端作为其他TLS聚合酶的支架蛋白。由于前者的活动，Rev 1绕过脱嘌呤/脱嘧啶位点，通过纳入dCMP，而后者的活动介导的组装在DNA损伤的多聚合酶复合物。我们在青鳉鱼中产生了缺乏这两种活性的drev 1突变体，并分析了烷化剂二乙基亚硝胺（DENA）的细胞毒性和致突变性。缺少C末端的突变体对DENA细胞毒性高度敏感，而具有降低的dCMP转移酶活性的突变体对DENA细胞毒性略微敏感，但表现出比野生型鱼更高的致瘤率。在具有降低的dCMP转移酶活性的突变体和野生型培养细胞之间，DENA诱导的突变频率没有显著差异。然而，杂合性丢失（洛）经常发生在细胞与dCMP转移酶活性降低。洛缺失（LOH）是多种肿瘤中常见的遗传事件，在肿瘤的发生发展中起重要作用。据我们所知，这是第一个报告，以确定参与的催化活性的Rev 1抑制洛。
Translesion synthesis (TLS) polymerases mediate DNA damage bypass during replication. The TLS polymerase Rev1 has two important functions in the TLS pathway, including dCMP transferase activity and acting as a scaffolding protein for other TLS polymerases at the C‐terminus. Because of the former activity, Rev1 bypasses apurinic/apyrimidinic sites by incorporating dCMP, whereas the latter activity mediates assembly of multipolymerase complexes at the DNA lesions. We generatedrev1mutants lacking each of these two activities inOryzias latipes(medaka) fish and analyzed cytotoxicity and mutagenicity in response to the alkylating agent diethylnitrosamine (DENA). Mutant lacking the C‐terminus was highly sensitive to DENA cytotoxicity, whereas mutant with reduced dCMP transferase activity was slightly sensitive to DENA cytotoxicity, but exhibited a higher tumorigenic rate than wild‐type fish. There was no significant difference in the frequency of DENA‐induced mutations between mutant with reduced dCMP transferase activity and wild‐type cultured cell. However, loss of heterozygosity (LOH) occurred frequently in cells with reduced dCMP transferase activity. LOH is a common genetic event in many cancer types and plays an important role on carcinogenesis. To our knowledge, this is the first report to identify the involvement of the catalytic activity of Rev1 in suppression of LOH.