Disruption of the developmentally regulated Rev31 gene causes embryonic lethality

The REV3 gene encodes the catalytic subunit of DNA polymerase (pol) zeta, w hich can replicate past certain types of DNA lesions [1], Saccharomyces cer evisiae rev3 mutants are viable and have lower rates of spontaneous and DNA -damage-induced mutagenesis [2], Reduction in the level of Rev31, the presu med catalytic subunit of mammalian pol zeta, decreased damage-induced mutag enesis in human cell lines [3]. To study the function of mammalian Rev31,we inactivated the gene in mice, Two exons containing conserved DNA polymeras e motifs were replaced by a cassette encoding G418 resistance and beta -gal actosidase, under the control of the Rev31 promoter. Surprisingly, disrupti on of Rev31 caused mid-gestation embryonic lethality, with the frequency of Rev31(-/-) embryos declining markedly between 9.5 and 12.5 days post coitu m (dpc), Rev31(-/-) embryos were smaller than their heterozygous littermate s 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 extraem bryonic membranes. Embryonic death coincided with the period of more widely distributed Rev31 expression. The data demonstrate an essential function f or murine Rev31 and suggest that bypass of specific types of DNA lesions by pol zeta is essential for cell viability during embryonic development in m ammals. (C) 2000 Elsevier Science Ltd. All rights reserved.