Rapid repair of UVA-induced oxidized purines and persistence of UVB-induced dipyrimidine lesions determine the mutagenicity of sunlight in mouse cells.
Despite the predominance of ultraviolet A (UVA) relative to UVB in terrestrial sunlight, solar mutagenesis in humans and rodents is characterized by mutations specific for UVB. We have investigated the kinetics of repair of UVA- and UVB-induced DNA lesions in relation to mutagenicity in transgenic mouse fibroblasts irradiated with equilethal doses of UVA and UVB in comparison to simulated-sunlight UV (SSL). We have also analyzed mutagenesis-derived carcinogenesis in sunlight-associated human skin cancers by compiling the published data on mutation types found in crucial genes in nonmelanoma and melanoma skin cancers. Here, we demonstrate a resistance to repair of UVB-induced cis-syn cyclobutane pyrimidine-dimers (CPDs) together with rapid removal of UVA-induced oxidized purines in the genome overall and in the cII transgene of SSL-irradiated cells. The spectra of mutation induced by both UVB and SSL irradiation in this experimental system are characterized by significant increases in relative frequency of C-->T transitions at dipyrimidines, which are the established signature mutation of CPDs. This type of mutation is also the predominant mutation found in human nonmelanoma and melanoma tumor samples in the TP53, CDKN2, PTCH, and protein kinase genes. The prevailing role of UVB over UVA in solar mutagenesis in our test system can be ascribed to different kinetics of repair for lesions induced by the respective UV irradiation.
Besaratinia
Ahmad
A
Division of Biology, Beckman Research Institute of the City of Hope National Medical Center, 1450 East Duarte Road, Duarte, CA 91010, USA. ania@coh.org
Kim
Sang-In
SI
Pfeifer
Gerd P
GP
D000818:Animals; D004249:DNA Damage / Q000528:radiation effects*; D004260:DNA Repair / Q000528:radiation effects*; D004307:Dose-Response Relationship, Radiation; D004622:Embryo, Mammalian; D016678:Genome / Q000528:radiation effects; D051379:Mice; D011687:Purines / Q000528:radiation effects*; D011743:Pyrimidines / Q000528:radiation effects*; D013472:Sunlight / Q000009:adverse effects*; D014466:Ultraviolet Rays / Q000009:adverse effects*
D011687:Purines; D011743:Pyrimidines