The Primary Role of Apurinic Sites in Tumor Initiation

Abstract

The profiles of DNA adducts determined for benzo[a]pyrene (BP), 7,12-dimethylbenz[a]anthracene (DMBA) and dibenzo[a,l]pyrene (DB[a,l]P) reveal that a majority of adducts are released from DNA by depurination. Papillomas were induced in mouse skin by several PAH, and mutations in the c-Harvey-ras oncogene were determined to investigate the relationship between DNA adducts and ras oncogene mutations. The pattern of mutations induced by each PAH correlated with the profile of depurinating adducts. DB[a,l]P and DMBA formed predominantly depurinating adenine adducts (78% and 79%, respectively) and consistently induced a CAA → CTA transversion in codon 61 of ras. In contrast, BP produced both guanine (46%) and adenine (25%) depurinating adducts and induced a GGC → GTC mutation in codon 13 of c-H-ras in 54% of tumors and a CAA → CTA mutation in codon 61 in 15% of tumors. These results support the hypothesis that mis-replication of unrepaired apurinic sites generated by loss of PAH-DNA adducts is responsible for transforming mutations leading to papillomas in mouse skin.

Key Words:

• PAH
• DNA adducts
• oncogenes
• mouse skin papillomas
• ras mutations