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DNA polymerase ζ limits chromosomal damage and promotes cell survival following aflatoxin exposure.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2016 Nov 29; Vol. 113 (48), pp. 13774-13779. Date of Electronic Publication: 2016 Nov 14. - Publication Year :
- 2016
-
Abstract
- Routine dietary consumption of foods that contain aflatoxins is the second leading cause of environmental carcinogenesis worldwide. Aflatoxin-driven mutagenesis is initiated through metabolic activation of aflatoxin B <subscript>1</subscript> (AFB <subscript>1</subscript> ) to its epoxide form that reacts with N7 guanine in DNA. The resulting AFB <subscript>1</subscript> -N7-dG adduct undergoes either spontaneous depurination or imidazole-ring opening yielding formamidopyrimidine AFB <subscript>1</subscript> (AFB <subscript>1</subscript> -Fapy-dG). Because this latter adduct is known to persist in human tissues and contributes to the high frequency G-to-T mutation signature associated with many hepatocellular carcinomas, we sought to establish the identity of the polymerase(s) involved in processing this lesion. Although our previous biochemical analyses demonstrated the ability of polymerase ζ (pol ζ) to incorporate an A opposite AFB <subscript>1</subscript> -Fapy-dG and extend from this mismatch, biological evidence supporting a unique role for this polymerase in cellular tolerance following aflatoxin exposure has not been established. Following challenge with AFB <subscript>1</subscript> , survival of mouse cells deficient in pol ζ (Rev3L <superscript>-/-</superscript> ) was significantly reduced relative to Rev3L <superscript>+/-</superscript> cells or Rev3L <superscript>-/-</superscript> cells complemented through expression of the wild-type human REV3L. Furthermore, cell-cycle progression of Rev3L <superscript>-/-</superscript> mouse embryo fibroblasts was arrested in late S/G2 following AFB <subscript>1</subscript> exposure. These Rev3L <superscript>-/-</superscript> cells showed an increase in replication-dependent formation of γ-H2AX foci, micronuclei, and chromosomal aberrations (chromatid breaks and radials) relative to Rev3L <superscript>+/-</superscript> cells. These data suggest that pol ζ is essential for processing AFB <subscript>1</subscript> -induced DNA adducts and that, in its absence, cells do not have an efficient backup polymerase or a repair/tolerance mechanism facilitating survival.<br />Competing Interests: The authors declare no conflict of interest.
- Subjects :
- Aflatoxin B1 analogs & derivatives
Aflatoxin B1 genetics
Aflatoxin B1 toxicity
Aflatoxins toxicity
Animals
Carcinoma, Hepatocellular chemically induced
Carcinoma, Hepatocellular pathology
Cell Survival drug effects
Chromosome Aberrations drug effects
Cytidine analogs & derivatives
Cytidine genetics
Cytidine toxicity
DNA Adducts drug effects
DNA Adducts genetics
DNA Damage drug effects
DNA Repair genetics
DNA-Directed DNA Polymerase chemistry
Fibroblasts drug effects
Fibroblasts metabolism
Humans
Liver Neoplasms chemically induced
Liver Neoplasms pathology
Mice
Mutagenesis drug effects
Mutagenesis genetics
Mutation
Carcinoma, Hepatocellular genetics
DNA-Binding Proteins genetics
DNA-Directed DNA Polymerase genetics
Liver Neoplasms genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 113
- Issue :
- 48
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 27849610
- Full Text :
- https://doi.org/10.1073/pnas.1609024113