Abstract
Treatment of SENCAR mouse skin with dibenzo[a,l]pyrene results in abundant formation of abasic sites that undergo error-prone excision repair, forming oncogenic H-ras mutations in the early preneoplastic period. To examine whether the abundance of abasic sites causes repair infidelity, we treated SENCAR mouse skin with estradiol-3,4-quinone (E2-3,4-Q) and determined adduct levels 1 h after treatment, as well as mutation spectra in the H-ras gene between 6 h and 3 days after treatment. E2-3,4-Q formed predominantly (⩾99%) the rapidly-depurinating 4-hydroxy estradiol (4-OHE2)-1-N3Ade adduct and the slower-depurinating 4-OHE2-1-N7Gua adduct. Between 6 h and 3 days, E2-3,4-Q induced abundant A to G mutations in H-ras DNA, frequently in the context of a 3′-G residue. Using a T.G-DNA glycosylase (TDG)-PCR assay, we determined that the early A to G mutations (6 and 12 h) were in the form of G.T heteroduplexes, suggesting misrepair at A-specific depurination sites. Since G-specific mutations were infrequent in the spectra, it appears that the slow rate of depurination of the N7Gua adducts during active repair may not generate a threshold level of G-specific abasic sites to affect repair fidelity. These results also suggest that E2-3,4-Q, a suspected endogenous carcinogen, is a genotoxic compound and could cause mutations.
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Acknowledgements
This research was supported by US Public Health Service grant P01 CA49210. Core support at the Eppley Institute was funded by NCI Laboratory Cancer Research Support (Core) grant CA 36727. The Washington University Mass Spectrometry laboratory is supported by the National Centers for Research Resources of the NIH (Grant No. P41 RR 00954).
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Chakravarti, D., Mailander, P., Li, KM. et al. Evidence that a burst of DNA depurination in SENCAR mouse skin induces error-prone repair and forms mutations in the H-ras gene. Oncogene 20, 7945–7953 (2001). https://doi.org/10.1038/sj.onc.1204969
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DOI: https://doi.org/10.1038/sj.onc.1204969
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