title: Transcription-dependent cytosine deamination is a novel mechanism in ultraviolet light-induced mutagenesis.
abstract: Skin cancer is the most ubiquitous cancer type in the Caucasian population, and its incidence is increasing rapidly [1]. Transcribed proliferation-related genes in dermal stem cells are targets for the induction of ultraviolet light (UV)-induced mutations that drive carcinogenesis. We have recently found that transcription of a gene increases its mutability by UV in mammalian stem cells, suggesting a role of transcription in skin carcinogenesis [2]. Here we show that transcription-associated UV-induced nucleotide substitutions are caused by increased deamination of cytosines to uracil within photolesions at the transcribed strand, presumably at sites of stalled transcription complexes. Additionally, via an independent mechanism, transcription of UV-damaged DNA induces the generation of intragenic deletions. We demonstrate that transcription-coupled nucleotide excision repair (TC-NER) provides protection against both classes of transcription-associated mutagenesis. Combined, these results unveil the existence of two mutagenic pathways operating specifically at the transcribed DNA strand of active genes. Moreover, these results uncover a novel role for TC-NER in the suppression of UV-induced genome aberrations and provide a rationale for the efficient induction of apoptosis by stalled transcription complexes.
authors.affiliation: Department of Toxicogenetics, Leiden University Medical Center (LUMC), PO Box 9600, 2300 RC, Leiden, The Netherlands.
authors.forename: Giel
authors.initials: G
authors.lastname: Hendriks
authors.forename: Fabienne
authors.initials: F
authors.lastname: Calléja
authors.forename: Ahmad
authors.initials: A
authors.lastname: Besaratinia
authors.forename: Harry
authors.initials: H
authors.lastname: Vrieling
authors.forename: Gerd P
authors.initials: GP
authors.lastname: Pfeifer
authors.forename: Leon H F
authors.initials: LH
authors.lastname: Mullenders
authors.forename: Jacob G
authors.initials: JG
authors.lastname: Jansen
authors.forename: Niels
authors.initials: N
authors.lastname: de Wind
mesh_terms: D003596:Cytosine / Q000378:metabolism*; D003641:Deamination; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D016296:Mutagenesis; D014158:Transcription, Genetic; D014466:Ultraviolet Rays
chemical_list: D003596:Cytosine; D007041:Hypoxanthine Phosphoribosyltransferase