Involvement of Rev1 in alkylating agent‐induced loss of heterozygosity in Oryzias latipes

• Published in: Genes to cells : devoted to molecular & cellular mechanisms 2020-02, Vol.25 (2), p.124-138
• Main Authors: Fujikawa, Yoshihiro, Ishikawa‐Fujiwara, Tomoko, Kuo, Tony, Shinkai, Norio, Shoji, Tatsuma, Kawasaki, Takashi, Kamei, Yasuhiro, Sakuraba, Yoshiyuki, Sato, Ayuko, Kinoshita, Masato, Gondo, Yoichi, Yuba, Shunsuke, Tsujimura, Tohru, Sese, Jun, Todo, Takeshi
• Format: Article
• Language: English
• Subjects: alkylating agent; Animals; Animals, Genetically Modified; Apyrimidinic sites; Carcinogenesis; Cell Line; chemical mutagenesis; Cytotoxicity; Deoxyribonucleic acid; Diethylnitrosamine; DNA; DNA biosynthesis; DNA Damage; DNA polymerase; DNA Repair; DNA Replication; DNA-Directed DNA Polymerase; Female; Gene Expression Regulation; Heterozygosity; Liver - pathology; Loss of Heterozygosity; Male; Mutagenesis; Mutagenicity; Mutants; Mutation; Nucleotidyltransferases - genetics; Nucleotidyltransferases - metabolism; Original; Oryzias - genetics; Oryzias latipes; Recombinant Proteins; Transcriptome; translesion synthesis
• ISSN: 1356-9597; 1365-2443
• DOI: 10.1111/gtc.12746

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. LOH is a common genetic event in many cancer types and plays an important role on carcinogenesis. We found defect in the catalytic activity of rev1 exhibited a higher tumorigenic rate and high frequency of LOH. To our knowledge, this is the first report to identify the involvement of the catalytic activity of Rev1 in suppression of LOH.