Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 113, Issue 48, Pages 13774-13779Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1609024113
Keywords
aflatoxin; mutagenesis; hepatocellular carcinogenesis; translesion DNA synthesis; environmental toxins
Categories
Funding
- National Institutes of Health [R01 CA055678, R01 CA132840]
- MD Anderson Research Trust
Ask authors/readers for more resources
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-1 (AFB(1)) to its epoxide form that reacts with N7 guanine in DNA. The resulting AFB(1)-N7-dG adduct undergoes either spontaneous depurination or imidazole-ring opening yielding formamidopyrimidine AFB(1) (AFB(1)-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 zeta (pol zeta) to incorporate an A opposite AFB(1)-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 AFB1, survival of mouse cells deficient in pol zeta (Rev3L(-/-)) was significantly reduced relative to Rev3L(+/-) cells or Rev3L(-/-) cells complemented through expression of the wild-type human REV3L. Furthermore, cell-cycle progression of Rev3L(-/-) mouse embryo fibroblasts was arrested in late S/G2 following AFB(1) exposure. These Rev3L(-/-) cells showed an increase in replication-dependent formation of gamma-H2AX foci, micronuclei, and chromosomal aberrations (chromatid breaks and radials) relative to Rev3L(+/-) cells. These data suggest that pol zeta is essential for processing AFB(1)-induced DNA adducts and that, in its absence, cells do not have an efficient backup polymerase or a repair/tolerance mechanism facilitating survival.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available