Loss of DNA Polymerase ζ Causes Chromosomal Instability in Mammalian Cells
- 1 January 2006
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 66 (1), 134-142
- https://doi.org/10.1158/0008-5472.can-05-2982
Abstract
Rev3L encodes the catalytic subunit of DNA polymerase ζ (pol ζ) in mammalian cells. In yeast, pol ζ helps cells bypass sites of DNA damage that can block replication enzymes. Targeted disruption of the mouse Rev3L gene causes lethality midway through embryonic gestation, and Rev3L−/− mouse embryonic fibroblasts (MEFs) remain in a quiescent state in culture. This suggests that pol ζ may be necessary for tolerance of endogenous DNA damage during normal cell growth. We report the generation of mitotically active Rev3L−/− MEFs on a p53−/− genetic background. Rev3L null MEFs exhibited striking chromosomal instability, with a large increase in translocation frequency. Many complex genetic aberrations were found only in Rev3L null cells. Rev3L null cells had increased chromosome numbers, most commonly near pentaploid, and double minute chromosomes were frequently found. This chromosomal instability associated with loss of a DNA polymerase activity in mammalian cells is similar to the instability associated with loss of homologous recombination capacity. Rev3L null MEFs were also moderately sensitive to mitomycin C, methyl methanesulfonate, and UV and γ-radiation, indicating that mammalian pol ζ helps cells tolerate diverse types of DNA damage. The increased occurrence of chromosomal translocations in Rev3L−/− MEFs suggests that loss of Rev3L expression could contribute to genome instability during neoplastic transformation and progression. (Cancer Res 2006; 66(1): 134-42)Keywords
This publication has 69 references indexed in Scilit:
- The Relative Roles in Vivo of Saccharomyces cerevisiae Pol η, Pol ζ, Rev1 Protein and Pol32 in the Bypass and Mutation Induction of an Abasic Site, T-T (6-4) Photoadduct and T-T cis-syn Cyclobutane DimerGenetics, 2005
- DNA Polymerase ζ Regulates Cisplatin Cytotoxicity, Mutagenicity, and The Rate of Development of Cisplatin ResistanceCancer Research, 2004
- Immortalized mouse cell lines that lack a functional Rev3 gene are hypersensitive to UV irradiation and cisplatin treatmentDNA Repair, 2004
- Mechanisms of DNA double strand break repair and chromosome aberration formationCytogenetic and Genome Research, 2004
- Eukaryotic DNA PolymerasesAnnual Review of Biochemistry, 2002
- The upr-1 gene encodes a catalytic subunit of the DNA polymerase ζ which is involved in damage-induced mutagenesis in Neurospora crassaMolecular Genetics and Genomics, 2002
- A full-length cDNA of hREV3 is predicted to encode DNA polymerase ζ for damage-induced mutagenesis in humansMutation Research/DNA Repair, 1999
- Molecular cloning, expression and chromosomal localisation of the mouse Rev3l gene, encoding the catalytic subunit of polymerase ζMutation Research/DNA Repair, 1999
- Deoxycytidyl transferase activity of yeast REV1 proteinNature, 1996
- Genetic analysis of γ-mutagenesis in yeast III. Double-mutant strainsMutation Research - Reviews in Mutation Research, 1980