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Recognition and repair of the cyclobutane thymine dimer, a major cause of skin cancers, by the human excision nuclease
Open accessAbstract
The cyclobutane thymine dimer is the major DNA lesion induced in human skin by sunlight and is a primary cause of skin cancer, the most prevalent form of cancer in the Northern Hemisphere. In humans, the only known cellular repair mechanism for eliminating the dimer from DNA is nucleotide excision repair. Yet the mechanism by which the dimer is recognized and removed by this repair system is not known. Here we demonstrate that the six-factor human excision nuclease recognizes and removes the dimer at a rate consistent with the in vivo rate of removal of this lesion, even though none of the six factors alone is capable of efficiently discriminating the dimer from undamaged DNA. We propose a recognition mechanism by which the low-specificity recognition factors, RPA, XPA, and XPC, act in a cooperative manner to locate the lesion and, aided by the kinetic proofreading provided by TFIIH, form a high-specificity complex at the damage site that initiates removal of thymine dimers at a physiologically relevant rate and specificity.
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“Importantly, the defects in components of the NER pathway result in Xeroderma pigmentosum (XP), Cockayne syndrome (CS), and trichothiodystrophy which are characterized by sensitivity to UV irradiation and predisposition to skin cancers [11, 12].”
From NER initiation factors, DDB2 and XPC, regulate UV radiation response by recruiting ATR and ATM kinases to DNA damage sites (2013) · cites this paper as [11]
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Metadata
- Authors
- Reardon, J. T., & Sancar, A.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Reardon, Joyce T.
- ORCID
- Sancar, Aziz
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2003-01-01
- Volume
- 17
- Issue
- 20
- Pages
- 2539-2551
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC218148
- OpenAlex
- W4298368564
- Cited by
- 179
- References
- 70
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 4 · 2023: 5 · 2022: 5 · 2021: 4 · 2020: 6 · 2019: 6 · 2018: 4 · 2017: 9 · 2016: 15 · 2015: 7 · 2014: 7 · 2013: 13 · 2012: 6
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- Kanazawa University
- National Institutes of Health
- University of Illinois at Urbana-Champaign
- University of North Carolina at Chapel Hill
- National Institute of General Medical Sciences (R01GM032833, GM32833)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Carcinogens and Genotoxicity Assessment
- Keywords
- cyclobutane thymine dimers, nucleotide excision repair, DNA damage recognition, skin cancer, UV-induced DNA damage, RPA, XPA, XPC, TFIIH, kinetic proofreading, cooperative recognition
- MeSH terms
- Deoxyribodipyrimidine Photo-Lyase, DNA Repair, Humans, Models, Molecular, DNA Ligases, Pyrimidine Dimers, Skin Neoplasms, Protein Structure, Tertiary
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