Two-step recognition of DNA damage for mammalian nucleotide excision repair: Directional binding of the XPC complex and DNA strand scanning
Open accessAbstract
For mammalian nucleotide excision repair (NER), DNA lesions are recognized in at least two steps involving detection of unpaired bases by the XPC protein complex and the subsequent verification of injured bases. Although lesion verification is important to ensure high damage discrimination and the accuracy of the repair system, it has been unclear how this is accomplished. Here, we show that damage verification involves scanning of a DNA strand from the site where XPC is initially bound. Translocation by the NER machinery exhibits a 5'-to-3' directionality, strongly suggesting involvement of the XPD helicase, a component of TFIIH. Furthermore, the initial orientation of XPC binding is crucial in that only one DNA strand is selected to search for the presence of lesions. Our results dissect the intricate molecular mechanism of NER and provide insights into a strategy for mammalian cells to survey large genomes to detect DNA damage.
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DDB2 and XPC have inherent recognition capacity for UVR-induced DNA damage and instigate prompt formation of pre-incision complex at damage sites.
“DDB2 and XPC have the inherent recognition capacity for UVR-induced DNA damage, and instigate the prompt formation of pre-incision complex at the damage sites [5;57–59].”
From ATR- and ATM-Mediated DNA Damage Response Is Dependent on Excision Repair Assembly during G1 but Not in S Phase of Cell Cycle (2016) · cites this paper as [58]
Superposition of Rad33 in the Rad33-Rad14 complex model onto the TFIIH/Rad4-Rad23-Rad33 initial recognition complex shows how Rad14 can interact with the Rad4-Rad23-Rad33 recognition complex while maintaining the TFIIH interaction, bridging the steps of initial damage recognition and damage verification.
“Superposition of Rad33 in the Rad33-Rad14 complex model onto this structure (Fig. 5D) shows how Rad14 can interact with the Rad4–Rad23–Rad33 recognition complex (38,42) while maintaining the TFIIH interaction, bridging the steps of initial damage recognition and damage verification.”
From Computed structures of core eukaryotic protein complexes (2021) · cites this paper as [38]
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References 57 · Cited by 205
- Authors
- Sugasawa, K., Akagi, J.-I., Nishi, R., Iwai, S., & Hanaoka, F.
- Affiliations
- Japan Science and Technology Agency (JP)
- The University of Osaka (JP)
- Corresponding author
- Sugasawa, Kaoru
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2009-11
- Volume
- 36
- Issue
- 4
- Pages
- 642-653
- ISSN
- 1097-2765 (ISSN-L)
- OpenAlex
- W2016874507
- Cited by
- 205
- References
- 57
- Citations by year
- 2026: 10 · 2025: 7 · 2024: 10 · 2023: 13 · 2022: 9 · 2021: 14 · 2020: 8 · 2019: 17 · 2018: 13 · 2017: 12 · 2016: 16 · 2015: 17 · 2014: 12 · 2013: 18 · 2012: 6
- FWCI
- 3.89
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Biosignal Research Center, Kobe University
- Japan Society for the Promotion of Science
- 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 › Molecular Biology › Diffusion and Search Dynamics
- Keywords
- nucleotide excision repair, XPD helicase, TFIIH, DNA damage recognition, DNA damage detection, unpaired bases, DNA damage tolerance
- MeSH terms
- Adenosine Triphosphatases, Cell Line, Cell-Free System, DNA, DNA Damage, DNA Repair, Humans, Models, Genetic, Nucleic Acid Conformation, Protein Binding, Pyrimidine Dimers, Xeroderma Pigmentosum, Transcription Factor TFIIH
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