The molecular pathways of ultraviolet-induced carcinogenesis.
Cancer development requires the accumulation of numerous genetic changes which are usually believed to occur through the presence of unrepaired DNA lesions. Exogenous or endogenous DNA-damaging agents can lead to mutations in the absence of efficient error-free repair, via replication of DNA damage. Several DNA repair pathways are present in living cells and well-conserved from bacteria to human cells. The nucleotide excision repair (NER), the most versatile of these DNA repair systems, recognizes and eliminates a wide variety of DNA lesions and particularly those induced by ultraviolet (UV) light. The phenotypic consequences of a NER defect in humans are apparent in rare but dramatic diseases characterized by hypersensitivity to UV and a striking clinical and genetic heterogeneity. The xeroderma pigmentosum (XP) syndrome is a human disorder inherited as an autosomal recessive trait. Persistence of unrepaired DNA damage produced by exposure to UV light is associated, in the XP syndrome, with an extremely high level of skin tumors in sun-exposed sites. Several key genes are mutagenized by UV-light and are responsible for skin cancer development. Mutations are found on ras oncogenes, p53 and PTCH tumour suppressor genes in skin cancers from DNA repair proficient as well as XP patients. The typical signature of UV-induced mutations found on these genes allows one to conclude that the uvB part of sunlight is responsible for the initiation of the carcinogenesis process.
Sarasin
A
A
Laboratory of Molecular Genetics, UPR 42, CNRS, 94801, Villejuif, France. sarasin@infobiogen.fr
D004249:DNA Damage; D004260:DNA Repair; D016158:Genes, p53; D011905:Genes, ras; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics; D009154:Mutation; D009369:Neoplasms / Q000209:etiology* / Q000235:genetics; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface; D012878:Skin Neoplasms / Q000209:etiology / Q000235:genetics; D014466:Ultraviolet Rays / Q000009:adverse effects*; D014983:Xeroderma Pigmentosum / Q000150:complications / Q000235:genetics
D008565:Membrane Proteins; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface