Mutagenic and tumorigenic study of Rev1, Y-family DNA polymerases, in vivo

Abstract

Purpose: Rev1, the member of the Y-family DNA polymerase, has deoxycytidyl transferase activity that incorporates dCMPs on the opposite to an abasic site. This study sought to determine how increasing Rev1 affects the mutagenicity and the frequency of tumor occurrence in a mouse model. Methods and Results: Rev1 transgenic mice carrying murine Rev1 cDNA under the metallothionein promoter and wild type mice (C57BL/6N) were treated with N -methyl-N -nitroso urea (MNU) and examined for their development of lymphoma and small intestinal tumor. We found that incidence of lymophoma increased in female Rev1 transgenic mice and that the number of small intestinal tumor increased in male Rev1 transgenic mice. Cell surface and molecular analyses of lymphoma cells revealed that tumors developed from various differentiation stages of T cells and in some case had point mutations in Ikaros or p53 genes, irrespectively of gender or Rev1 statuses. We also found that the number of small intestinal tumor per mouse increased in Rev1 homozygous compared with that of wild type and Rev1 hemizygous mice. These results suggest that Rev1 may enhance the susceptibility to MNU tumorigenicity in gene-dose dependent manner in vivo.