Evidence that error-prone DNA repair converts dibenzo[a,l]pyrene-induced depurinating lesions into mutations: formation, clonal proliferation and regression of initiated cells carrying H-ras oncogene mutations in early preneoplasia

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

“…One mutation (A 228 to G) among 36 plasmids (mutation frequency=5.5610 75 ) was observed. This result compares well with that from our previous determination of the frequency of spontaneous artifact mutations by 8 : 1 Tth and Vent DNA polymerase in the H-ras gene (6610 75 ) (Chakravarti et al, 2000). E 2 -3,4-Q treatment of mouse skin produced both depurinating (499%) and stable (51%) DNA adducts ( Table 1) that would induce excision repair.…”

“…Our results suggest that within 4 h of treating mouse skin with 200 nmol of DB[a,l]P, a bolus of approximately 200 000 depurinations/cell is formed . Repair produced error-induced mismatched heteroduplexes within 24 h after treatment with DB[a,l]P (Chakravarti et al, 2000). We, therefore, hypothesize that in mouse skin, abundant depurination is a factor that a ects the ®delity of abasic site repair.…”

“…Carcinogen-induced DNA damage causes cells to enter into a period of replication block (Slaga et al, 1973(Slaga et al, , 1974 and repair induction (Sawyer et al, 1988;Gill et al, 1991) before continuing with the cell cycle (Kaufmann, 1995;Maher and McCormick, 1987). Oncogenic mutations may arise from errors committed during pre-replication repair (Chakravarti et al, 1998b(Chakravarti et al, , 2000 and, also, during subsequent replication in cells harboring unrepaired DNA lesions (Maher and McCormick, 1987;Kaufmann, 1995;Moriya et al, 1996).…”

“…AP sites generated by these depurinating adducts induce pre-replication repair that is error-prone and forms mismatched heteroduplexes leading to transforming mutations in the H-ras gene at codon 61 (CAA to CTA) (Chakravarti et al, 1998b(Chakravarti et al, , 2000. In contrast, a metabolite of DB[a,l]P, (+)-anti-DB[a,l]P-11,12-diol-13,14-epoxide (anti-DB[a,l]PDE), which forms 97% stable adducts in mouse skin , does not appear to induce mismatched heteroduplexes in these early preneoplastic stages (Chakravarti et al, 2000). PAH-induced stably adducted DNA is thought to undergo error-free NER (Watanabe et al, 1985;Choi et al, 1996).…”

Cigarette smoke condensate-induced level of adenomatous polyposis coli blocks long-patch base excision repair in breast epithelial cells

“…Cigarette smoke carcinogens require metabolic activation to form intermediates that are often more reactive than the parent compound and can form DNA adducts (Chakravarti et al, 2000;Hecht, 2002). Individual cigarette smoke carcinogens such as polycyclic hydrocarbons benzo[a]pyrene (B[a]P), 7,12-dimethylbenz(a)anthracine (DMBA) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) have been found to transform cultured cells and/or induce mammary tumors in mammals (Soule et al, 1990;el-Bayoumay et al, 1995;Mei et al, 2003;Currier et al, 2005).…”