Transcription-Dependent Cytosine Deamination Is a Novel Mechanism in Ultraviolet Light-Induced Mutagenesis

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...

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Bibliographic Details
Published in:Current biology 2010-01, Vol.20 (2), p.170-175
Main Authors: Hendriks, Giel, Calléja, Fabienne, Besaratinia, Ahmad, Vrieling, Harry, Pfeifer, Gerd P., Mullenders, Leon H.F., Jansen, Jacob G., de Wind, Niels
Format: Article
Language:English
Subjects:
Cytosine - metabolism
Deamination
DNA
Hypoxanthine Phosphoribosyltransferase - genetics
Mutagenesis
Transcription, Genetic
Ultraviolet Rays
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Summary: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. ► Transcribed genes are specific targets for ultraviolet light-induced mutagenesis ► Gene transcription increases frequencies of two types of UV light-induced mutations ► Cytosines at photolesions at the transcribed strand are preferentially deaminated ► Transcription-coupled DNA repair counteracts transcription-associated mutagenesis
ISSN:0960-9822
1879-0445
DOI:10.1016/j.cub.2009.11.061