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- Title
Preferential DNA damage and poor repair determine ras gene mutational hotspot in human cancer.
- Authors
Feng, Zhaohui; Hu, Wenwei; Chen, James X; Pao, Annie; Li, Haiying; Rom, William; Hung, Mien-Chie; Tang, Moon-shong
- Abstract
<bold>Background: </bold>Mutations in ras genes are commonly found in human cancers and in animal models. Although mutations at codons 12, 13, and 61 of H-, N- and K-ras genes can activate their oncogenic function, mutations at codon 12 of K-ras are the most common mutations found among the three ras genes in human cancers. To investigate whether codon 12 of human K-ras is especially susceptible to carcinogens and/or whether carcinogen-DNA adducts at this codon are repaired less efficiently, we examined tobacco smoke carcinogen-induced DNA damage in normal human bronchial epithelial and fibroblast cells.<bold>Methods: </bold>We used the UvrABC nuclease incision method in combination with ligation-mediated polymerase chain reaction to map the distribution of DNA adducts induced by benzo[a]pyrene diol epoxide (BPDE) and other bulky carcinogens within exons 1 and 2 in H-ras, N-ras, and K-ras. We also analyzed BPDE-DNA adduct repair efficiency in these three genes using the same method.<bold>Results: </bold>Codons 12 and 14 of the K-ras gene were hotspots for carcinogen-DNA adduct formation, with little and no adduct formation at codons 13 and 61, respectively. The BPDE-DNA adducts formed at codon 14 were repaired almost twice as quickly as those formed at codon 12. There was some BPDE-DNA adduct formation at codons 12 of H-ras and N-ras, but this codon was not a hotspot. Furthermore, no substantial difference in repair rates between codon 12 and the other codons analyzed (codons 3 and 18) was observed in either the H-ras or N-ras genes.<bold>Conclusion: </bold>These findings link the human cancer mutational hotspot at codon 12 of K-ras to preferential DNA damage and poor repair.
- Publication
JNCI: Journal of the National Cancer Institute, 2002, Vol 94, Issue 20, p1527
- ISSN
0027-8874
- Publication type
journal article