title: Transcription-coupled repair and apoptosis provide specific protection against transcription-associated mutagenesis by ultraviolet light.
abstract: Recent data reveal that gene transcription affects genome stability in mammalian cells. For example, transcription of DNA that is damaged by the most prevalent exogenous genotoxin, UV light, induces nucleotide substitutions and chromosomal instability, collectively called UV-induced transcription-associated mutations (UV-TAM). An important class of UV-TAM consists of nucleotide transitions that are caused by deamination of cytosine-containing photolesions to uracil, presumably occurring at stalled transcription complexes. Transcription-associated deletions and recombinational events after UV exposure may be triggered by collisions of replication forks with stalled transcription complexes. In this Point-of-View we propose that mammalian cells possess two tailored mechanisms to prevent UV-TAM in dermal stem cells. First, the transcription-coupled nucleotide excision repair (TCR) pathway removes lesions at transcribed DNA strands, forming the primary barrier against the mutagenic consequences of transcription at a damaged template. Second, when TCR is absent or when the capacity of TCR is exceeded, persistently stalled transcription complexes induce apoptosis, averting the generation of mutant cells following replication. We hypothesize that TCR and the apoptotic response in conjunction reduce the risk of skin carcinogenesis.
authors.affiliation: Leiden University Medical Center, The Netherlands.
authors.forename: Giel
authors.initials: G
authors.lastname: Hendriks
authors.forename: Jacob G
authors.initials: JG
authors.lastname: Jansen
authors.forename: Leon H F
authors.initials: LH
authors.lastname: Mullenders
authors.forename: Niels
authors.initials: N
authors.lastname: de Wind
mesh_terms: D000818:Animals; D017209:Apoptosis; D004249:DNA Damage; D004260:DNA Repair; D006801:Humans; D008957:Models, Genetic; D016296:Mutagenesis / Q000235:genetics / Q000528:radiation effects*; D014158:Transcription, Genetic / Q000235:genetics*; D014466:Ultraviolet Rays