UVB-induced cyclobutane pyrimidine dimer frequency correlates with skin cancer mutational hotspots in p53.
Ultraviolet light has been identified as the major carcinogen in skin cancer and the p53 tumor suppressor gene is a major target for UV-induced mutations. The mutations are probably caused by unrepaired UV-induced cyclobutane pyrimidine dimers (CPD) and possibly by the less frequent pyrimidine (6-4) pyrimidone photoproducts. While hot spots for p53 mutations in human nonmelanoma skin tumors correspond quite well to slow spots for CPD repair in cultured cells irradiated with the model mutagen 254 nm UVC (which is not present in terrestrial sunlight), they do not all coincide with sequences that are initially frequently damaged by 254 nm UVC. Using LMPCR (ligation-mediated polymerase chain reaction), we show that environmentally relevant UVB light induces CPD at CC and Pyr(m)C positions much more frequently than does UVC light, and that all eight skin cancer hot spots in p53 are also hot spots for UVB-induced CPD. Our results show that methylation of dipyrimidine sites (Pyr(m)CpG) is associated with an increase rate of CPD formation upon UVB irradiation. Consequently, DNA methylation may increase the mutagenic potential of UVB and explains that several p53 mutation hot spots are found at Pyr(m)CpG. The distribution patterns of CPD formation and the photofootprint patterns found along exons 5 and 6 of p53 gene are suggestive of DNA folding into nucleosomes.
Drouin
R
R
Department of Medical Biology, Université Laval, Québec, Canada. regen.drouin@crsfa.ulaval.ca
Therrien
J P
JP
D001483:Base Sequence; D002478:Cells, Cultured; D004247:DNA / Q000737:chemistry / Q000235:genetics / Q000528:radiation effects; D016158:Genes, p53 / Q000528:radiation effects*; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D009381:Neoplasms, Radiation-Induced / Q000209:etiology* / Q000235:genetics; D011740:Pyrimidine Dimers / Q000737:chemistry / Q000528:radiation effects*; D012878:Skin Neoplasms / Q000209:etiology* / Q000235:genetics; D014466:Ultraviolet Rays
D011740:Pyrimidine Dimers; D004247:DNA