Disruption of the developmentally regulated Rev31 gene causes embryonic lethality

The REV3 gene encodes the catalytic subunit of DNA polymerase (pol) zeta, which can replicate past certain types of DNA lesions [1], Saccharomyces cerevisiae rev3 mutants are viable and have lower rates of spontaneous and DNA-damage-induced mutagenesis [2], Reduction in the level of Rev31, the presumed catalytic subunit of mammalian pol zeta, decreased damage-induced mutagenesis in human cell lines [3]. To study the function of mammalian Rev31,we inactivated the gene in mice, Two exons containing conserved DNA polymerase motifs were replaced by a cassette encoding G418 resistance and beta -galactosidase, under the control of the Rev31 promoter. Surprisingly, disruption of Rev31 caused mid-gestation embryonic lethality, with the frequency of Rev31(-/-) embryos declining markedly between 9.5 and 12.5 days post coitum (dpc), Rev31(-/-) embryos were smaller than their heterozygous littermates and showed retarded development. Tissues in many areas were disorganised, with significantly reduced cell density, Rev31 expression, traced by beta -galactosidase staining, was first detected during early somitogenesis and gradually expanded to other tissues of mesodermal origin, including extraembryonic membranes. Embryonic death coincided with the period of more widely distributed Rev31 expression. The data demonstrate an essential function for murine Rev31 and suggest that bypass of specific types of DNA lesions by pol zeta is essential for cell viability during embryonic development in mammals. (C) 2000 Elsevier Science Ltd. All rights reserved.