Ultraviolet-B-light-induced mutagenesis of C-H-ras codons 11 and 12 in human skin fibroblasts.
Mutations in the ras oncogene are detected with a high frequency in non-melanoma skin cancer. Approximately half of the squamous-cell carcinomas (SCC) and one third of the basal-cell carcinomas (BCC) carry mutations at the second position of Ha-ras codon 12 (GGC to GTC), whereas mutations in Ki-ras codon 12 occur less frequently. Since the mutations in the Ha-ras and Ki-ras oncogenes are located opposite potential pyrimidine dimer sites (C-C), it is likely that the mutations are induced by ultraviolet radiation present in sunlight. We studied the capacity of ultraviolet B (UVB) light to induce base-pair changes in Ha-ras codons 11 and 12 in human skin fibroblasts. UVB induced mostly C to T and G to A transitions and C to A and G to T transversions. The base-pair change with the highest relative abundance was C to T in the middle position of codon 11 followed by (in diminishing relative abundance) C to A in the middle position of codon 11, G to A and G to T in the middle position of codon 12. The C to T and G to A transitions are compatible with pyrimidine photodimers as pre-mutagenic lesions, whereas the C to A and G to T transversions could be generated due to the formation of 8-hydroxyguanine, which is the major oxidation product of guanine. The relative abundance of mutations induced by UVB in Ha-ras codons 11 and 12 does not correlate with mutations observed in the DNA from non-melanoma skin cancer, where the G to T transversion in the middle position of codon 12 is selected.
Amstad
P A
PA
Department of Pathology, University of Maryland, Baltimore 21201-1192, USA.
Cerutti
P A
PA
D001483:Base Sequence; D002478:Cells, Cultured; D003062:Codon; D017931:DNA Primers / Q000737:chemistry; D005347:Fibroblasts; D011905:Genes, ras / Q000528:radiation effects*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D016296:Mutagenesis; D012150:Polymorphism, Restriction Fragment Length; D012867:Skin / Q000528:radiation effects*; D014466:Ultraviolet Rays
D003062:Codon; D017931:DNA Primers