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Molecular and Cellular Biology, April 2002, p. 2159-2169, Vol. 22, No. 7
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.7.2159-2169.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Involvement of Mouse Rev3 in Tolerance of Endogenous and Exogenous DNA Damage

Petra P. H. Van Sloun,,{dagger} Isabelle Varlet, Edwin Sonneveld, Jan J. W. A. Boei, Ron J. Romeijn, Jan C. J. Eeken, and Niels De Wind*

Department of Radiation Genetics and Chemical Mutagenesis, Leiden University Medical Center, 2300 RA Leiden, The Netherlands

Received 17 August 2000/ Returned for modification 30 August 2000/ Accepted 20 December 2001

The Rev3 gene of Saccharomyces cerevisiae encodes the catalytic subunit of DNA polymerase {zeta} that is implicated in mutagenic translesion synthesis of damaged DNA. To investigate the function of its mouse homologue, we have generated mouse embryonic stem cells and mice carrying a targeted disruption of Rev3. Although some strain-dependent variation was observed, Rev3-/- embryos died around midgestation, displaying retarded growth in the absence of consistent developmental abnormalities. Rev3-/- cell lines could not be established, indicating a cell-autonomous requirement of Rev3 for long-term viability. Histochemical analysis of Rev3-/- embryos did not reveal aberrant replication or cellular proliferation but demonstrated massive apoptosis in all embryonic lineages. Although increased levels of p53 are detected in Rev3-/- embryos, the embryonic phenotype was not rescued by the absence of p53. A significant increase in double-stranded DNA breaks as well as chromatid and chromosome aberrations was observed in cells from Rev3-/- embryos. The inner cell mass of cultured Rev3-/- blastocysts dies of a delayed apoptotic response after exposure to a low dose of N-acetoxy-2-acetylaminofluorene. These combined data are compatible with a model in which, in the absence of polymerase {zeta}, double-stranded DNA breaks accumulate at sites of unreplicated DNA damage, eliciting a p53-independent apoptotic response. Together, these data are consistent with involvement of polymerase {zeta} in translesion synthesis of endogenously and exogenously induced DNA lesions.

* Corresponding author. Mailing address: Department of Radiation Genetics and Chemical Mutagenesis, Leiden University Medical Center, 2300 RA Leiden, The Netherlands. Phone: 31715271607. Fax: 31715276173. E-mail: N.de_Wind{at}LUMC.nl.

{dagger} Present address: Department of Molecular Haematology, J. W. G. University, D-60596 Frankfurt am Main, Germany.

Molecular and Cellular Biology, April 2002, p. 2159-2169, Vol. 22, No. 7
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.7.2159-2169.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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