title: Mutations induced by ultraviolet light.
abstract: The different ultraviolet (UV) wavelength components, UVA (320-400 nm), UVB (280-320 nm), and UVC (200-280 nm), have distinct mutagenic properties. A hallmark of UVC and UVB mutagenesis is the high frequency of transition mutations at dipyrimidine sequences containing cytosine. In human skin cancers, about 35% of all mutations in the p53 gene are transitions at dipyrimidines within the sequence 5'-TCG and 5'-CCG, and these are localized at several mutational hotspots. Since 5'-CG sequences are methylated along the p53 coding sequence in human cells, these mutations may be derived from sunlight-induced pyrimidine dimers forming at sequences that contain 5-methylcytosine. Cyclobutane pyrimidine dimers (CPDs) form preferentially at dipyrimidines containing 5-methylcytosine when cells are irradiated with UVB or sunlight. In order to define the contribution of 5-methylcytosine to sunlight-induced mutations, the lacI and cII transgenes in mouse fibroblasts were used as mutational targets. After 254 nm UVC irradiation, only 6-9% of the base substitutions were at dipyrimidines containing 5-methylcytosine. However, 24-32% of the solar light-induced mutations were at dipyrimidines that contain 5-methylcytosine and most of these mutations were transitions. Thus, CPDs forming preferentially at dipyrimidines with 5-methylcytosine are responsible for a considerable fraction of the mutations induced by sunlight in mammalian cells. Using mouse cell lines harboring photoproduct-specific photolyases and mutational reporter genes, we showed that CPDs (rather than 6-4 photoproducts or other lesions) are responsible for the great majority of UVB-induced mutations. An important component of UVB mutagenesis is the deamination of cytosine and 5-methylcytosine within CPDs. The mutational specificity of long-wave UVA (340-400 nm) is distinct from that of the shorter wavelength UV and is characterized mainly by G to T transversions presumably arising through mechanisms involving oxidized DNA bases. We also discuss the role of DNA damage-tolerant DNA polymerases in UV lesion bypass and mutagenesis.
authors.affiliation: Department of Biology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA. gpfeifer@coh.org
authors.forename: Gerd P
authors.initials: GP
authors.lastname: Pfeifer
authors.forename: Young-Hyun
authors.initials: YH
authors.lastname: You
authors.forename: Ahmad
authors.initials: A
authors.lastname: Besaratinia
mesh_terms: D044503:5-Methylcytosine / Q000378:metabolism; D000818:Animals; D006801:Humans; D008545:Melanoma / Q000209:etiology / Q000235:genetics; D009154:Mutation; D009381:Neoplasms, Radiation-Induced / Q000235:genetics; D011740:Pyrimidine Dimers; D012878:Skin Neoplasms / Q000209:etiology / Q000235:genetics; D014466:Ultraviolet Rays
chemical_list: D011740:Pyrimidine Dimers; D044503:5-Methylcytosine