Transcription-Dependent Cytosine Deamination Is a Novel Mechanism in Ultraviolet Light-Induced Mutagenesis
Open accessAbstract
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.
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In cells, deamination efficiency can be modulated by RNA polymerase stalling at CPD sites during transcription.
“Recently, it was shown that the efficiency of the reaction can be modulated in cells by processes such as stalling of RNA polymerase at CPD sites during transcription (58).”
From Photoinduced Damage to Cellular DNA: Direct and Photosensitized Reactions<sup>†</sup> (2012) · cites this paper as [58]
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- Authors
- Hendriks, G., Calléja, F., Besaratinia, A., Vrieling, H., Pfeifer, G. P., Mullenders, L. H. F., Jansen, J. G., & de Wind, N.
- Affiliations
- Leiden University Medical Center (NL)
- City Of Hope National Medical Center (US)
- Venue
- Current Biology
- Publisher
- Elsevier BV
- Published
- 2010-01
- Volume
- 20
- Issue
- 2
- Pages
- 170-175
- ISSN
- 0960-9822 (ISSN-L)
- PMC
- PMC2818831
- OpenAlex
- W2074858286
- Cited by
- 39
- References
- 23
- Citations by year
- 2026: 1 · 2023: 1 · 2021: 4 · 2020: 1 · 2019: 1 · 2018: 2 · 2017: 2 · 2016: 3 · 2015: 3 · 2014: 3 · 2013: 2 · 2012: 8
- FWCI
- 2.35
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Current Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- Funders
- KWF Kankerbestrijding
- Leids Universitair Medisch Centrum
- National Institutes of Health
- National Institute of Environmental Health Sciences (R37ES006070, R01ES006070, ES-06070)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Carcinogens and Genotoxicity Assessment
- Health Sciences › Medicine › Dermatology › Skin Protection and Aging
- Keywords
- cytosine deamination, transcription-coupled repair, skin carcinogenesis, intragenic deletion, nucleotide substitution, dermal stem cells, apoptosis
- MeSH terms
- Cytosine, Deamination, Hypoxanthine Phosphoribosyltransferase, Transcription, Genetic, Ultraviolet Rays, Mutagenesis
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