Abstract
We have generated cell lines and mice with deletions in the Rev1 and Rev3 translesion synthesis (TLS) polymerases. Cell lines with a deletion of the Brct domain of Rev1 are marginally hypersensitivity to genotoxic agents. UV light-induced mutagenesis was reduced in these cells, most significantly at TT dimers. UV induced many chromatid aberrations, but no increase in sister chromatid exchanges, in a subset of cells only. Remarkably, mice with the Rev1 Brct deletion display accelerated UV-induced tumorigenesis. Complete disruption of Rev1 confers sensitivity to all genotoxic agents tested, indicating a role for the protein in TLS beyond its dCTP transferase activity. Rev1-deficient mice are born in a sub-Mendelian ratio, are small, nearly infertile and are hypersensitive to UV. Rev3 deficiency results in embryonic lethality at mid-gestation accompanied with chromatid and chromosome aberrations. This phenotype could partially be rescued by introducing deficiency for DNA mismatch repair. Rev3-deficient primary fibroblasts display an S phase arrest and premature senescence; immortalized Rev3-deficient fibroblasts are extremely sensitive to all genotoxic agents tested. Together these data are consistent with a role of Rev1 and Rev3 in the mutagenic replication of endogenous and exogenous DNA damage, averting DNA damage-induced cell cycle arrests and cytogenetic aberrations. In addition, DNA mismatch repair appears an important player in eliciting these responses induced by endogenous DNA damage.
