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 generated rev1 mutants lacking each of these two activities in Oryzias 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.

中文翻译：

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Rev1参与烷基化剂诱导的稻（Oryzias latipes）杂合性丧失。

跨病变合成（TLS）聚合酶在复制过程中介导DNA损伤旁路。TLS聚合酶Rev1在TLS途径中具有两个重要功能，包括dCMP转移酶活性和在C端充当其他TLS聚合酶的支架蛋白。由于前者的活性，Rev1通过掺入dCMP绕过了嘌呤/嘧啶啶的位点，而后者的活性介导了DNA损伤处多聚酶复合物的组装。我们产生了rev1突变体，在稻（Olyzias latipes，medaka）鱼中缺少这两种活性，并且分析了对烷基化剂二乙基亚硝胺（DENA）的细胞毒性和致突变性。缺少C端的突变体对DENA细胞毒性高度敏感，而dCMP转移酶活性降低的突变体对DENA细胞毒性稍敏感，但显示出比野生鱼更高的致瘤率。在dCMP转移酶活性降低的突变体与野生型培养细胞之间，DENA诱导的突变频率没有显着差异。但是，杂合性（LOH）的丢失经常发生在具有降低的dCMP转移酶活性的细胞中。LOH是许多癌症类型中常见的遗传事件，并且在致癌作用中起重要作用。据我们所知，这是第一份鉴定Rev1催化活性参与LOH抑制的报告。dCMP转移酶活性降低的细胞中经常发生杂合性（LOH）丢失。LOH是许多癌症类型中常见的遗传事件，并且在致癌作用中起重要作用。据我们所知，这是第一份鉴定Rev1催化活性参与LOH抑制的报告。dCMP转移酶活性降低的细胞中经常发生杂合性（LOH）丢失。LOH是许多癌症类型中常见的遗传事件，并且在致癌作用中起重要作用。据我们所知，这是第一个鉴定Rev1催化活性参与LOH抑制的报告。