Relating aromatic hydrocarbon-induced DNA adducts and c-H-ras mutations in mouse skin papillomas: The role of apurinic sites

Dhrubajyoti Chakravarti, Jill C. Felling, Ercole L. Cavalieri, Eleanor G. Rogan

Research output: Contribution to journalArticlepeer-review

189 Scopus citations

Abstract

Mouse skin tumors contain activated c-H-ras oncogenes, often caused by point mutations at codons 12 and 13 in exon 1 and codons 59 and 61 in exon 2. Mutagenesis by the noncoding apurinic sites can produce G → T and A → T transversions by DNA misreplication with more frequent insertion of deoxyadenosine opposite the apurinic site. Papillomas were induced in mouse skin by several aromatic hydrocarbons, and mutations in the c-H-ras gene were determined to elucidate the relationship among DNA adducts, apurinic sites, and ras oncogene mutations. Dibenzo[a,l]pyrene (DB[a,l]P), DB[a,l]P-11,12- dihydrodiol, anti-DB[a,l]P-11,12-diol-13,14-epoxide, DB[a,l]P-8,9- dihydrodiol, 7,12-dimethylbenz[a]anthracene (DMBA), and 1,2,3,4-tetrahydro- DMBA consistently induced a CAA → CTA mutation in codon 61 of the c-H-ras oncogene. Benzo[a]pyrene induced a GGC → GTC mutation in codon 13 in 54% of tumors and a CAA → CTA mutation in codon 61 in 15%. The pattern of mutations induced by each hydrocarbon correlated with its profile of DNA adducts. For example, both DB[a,l]P and DMBA primarily form DNA adducts at the N-3 and/or N-7 of deoxyadenosine that are lost from the DNA by depurination, generating apurinic sites. Thus, these results support the hypothesis that misreplication of unrepaired apurinic sties generated by loss of hydrocarbon- DNA adducts is responsible for transforming mutations leading to papillomas in mouse skin.

Original languageEnglish (US)
Pages (from-to)10422-10426
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume92
Issue number22
DOIs
StatePublished - Oct 24 1995

ASJC Scopus subject areas

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