RRC ID 59228
Author 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.
Title Involvement of Rev1 in alkylating agent-induced loss of heterozygosity in Oryzias latipes.
Journal Genes Cells
Abstract 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.
Volume 25(2)
Pages 124-138
Published 2020-2-1
DOI 10.1111/gtc.12746
PMID 31917895
PMC PMC7079036
MeSH Animals Animals, Genetically Modified Carcinogenesis Cell Line DNA Damage DNA Repair DNA Replication DNA-Directed DNA Polymerase Female Gene Expression Regulation Liver / pathology Loss of Heterozygosity* Male Mutagenesis Mutation Nucleotidyltransferases / genetics* Nucleotidyltransferases / metabolism* Oryzias / genetics* Recombinant Proteins Transcriptome
IF 1.655
Times Cited 0
Medaka cDNA clone (Ole17.04a) TILLING_MUTANT Cab inbred line