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Evidence that a burst of DNA depurination in SENCAR mouse skin induces error-prone repair and forms mutations in the H-ras gene

2001; Springer Nature; Volume: 20; Issue: 55 Linguagem: Inglês

10.1038/sj.onc.1204969

1476-5594

Dhrubajyoti Chakravarti, Paula C. Mailander, Kai-Ming Li, Sheila Higginbotham, Henry L Zhang, Michael L. Gross, Jane L. Meza, Ercole L. Cavalieri, Eleanor G. Rogan,

Cancer-related Molecular Pathways

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.