Cited by 179DNA Repair MechanismsDNA and Nucleic Acid ChemistryCarcinogens and Genotoxicity Assessment

Recognition and repair of the cyclobutane thymine dimer, a major cause of skin cancers, by the human excision nuclease

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Reardon, Joyce T., Sancar, Aziz·2003·Genes & Development

Abstract

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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  1. Ptashne, M. and Gann, A. 2002. Genes & signals. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY.

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Authors
Reardon, J. T., & Sancar, A.
Affiliations
University of North Carolina at Chapel Hill (US)
Corresponding author
Reardon, Joyce T.
Venue
Genes & Development
Published
2003-01-01
Volume
17
Issue
20
Pages
2539-2551
ISSN
  • 0890-9369 (ISSN-L)
  • 1549-5477
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
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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