Published online 2 November 2004
Nucleic Acids Research, Vol. 32 No. 19 © Oxford University Press 2004; all rights reserved
REV1 accumulates in DNA damage-induced nuclear foci in human cells and is implicated in mutagenesis by benzo[a]pyrenediolepoxide
1 Department of Pharmacology and Toxicology, 2 Department of Medicine, 3 Molecular Targets Group, 4 Biomarkers, Chemoprevention and Genetics Group, James Graham Brown Cancer Center and 5 Center for Genetics and Molecular Medicine, University of Louisville, Louisville, KY, USA
* To whom correspondence should be addressed at 221 A Donald Baxter Biomedical Research Building, 570 S. Preston Street, University of Louisville Medical Center, Louisville, KY 40202-1786, USA. Tel: +1 502 852 2564; Fax: +1 502 852 2492; Email: wgmcgregor{at}louisville.edu
Received September 10, 2004; Revised and Accepted October 5, 2004
The REV1 gene encodes a Y-family DNA polymerase that has been postulated to have both catalytic and structural functions in translesion replication past UV photoproducts in mammalian cells. To examine if REV1 is implicated in DNA damage tolerance mechanisms after exposure of human cells to a chemical carcinogen, we generated a plasmid expressing REV1 protein fused at its C-terminus with green fluorescent protein (GFP). In transient transfection experiments, virtually all of the transfected cells had a diffuse nuclear pattern in the absence of carcinogen exposure. In contrast, in cells exposed to benzo[a]pyrenediolepoxide, the fusion protein accumulated in a focal pattern in the nucleus in 25% of the cells, and co-localized with PCNA. These data support the idea that REV1 is present at stalled replication forks. We also examined the mutagenic response at the HPRT locus of human cells that had greatly reduced levels of REV1 mRNA due to the stable expression of gene-specific ribozymes, and compared them to wild-type cells. The mutant frequency was greatly reduced in the ribozyme-expressing cells. These data indicate that REV1 is implicated in the mutagenic DNA damage tolerance response to BPDE and support the development of strategies to target this protein to prevent such mutations.
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