DDB accumulates at DNA damage sites immediately after UV irradiation and directly stimulates nucleotide excision repair
Open accessAbstract
Damaged DNA-binding protein, DDB, is a heterodimer of p127 and p48 with a high specificity for binding to several types of DNA damage. Mutations in the p48 gene that cause the loss of DDB activity were found in a subset of xeroderma pigmentosum complementation group E (XP-E) patients and have linked to the deficiency in global genomic repair of cyclobutane pyrimidine dimers (CPDs) in these cells. Here we show that with a highly defined system of purified repair factors, DDB can greatly stimulate the excision reaction reconstituted with XPA, RPA, XPC.HR23B, TFIIH, XPF.ERCC1 and XPG, up to 17-fold for CPDs and approximately 2-fold for (6-4) photoproducts (6-4PPs), indicating that no additional factor is required for the stimulation by DDB. Transfection of the p48 cDNA into an SV40-transformed human cell line, WI38VA13, was found to enhance DDB activity and the in vivo removal of CPDs and 6-4PPs. Furthermore, the combined technique of recently developed micropore UV irradiation and immunostaining revealed that p48 (probably in the form of DDB heterodimer) accumulates at locally damaged DNA sites immediately after UV irradiation, and this accumulation is also observed in XP-A and XP-C cells expressing exogenous p48. These results suggest that DDB can rapidly translocate to the damaged DNA sites independent of functional XPA and XPC proteins and directly enhance the excision reaction by core repair factors.
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In global genomic NER (GG-NER), damage is recognized by the DDB complex involving DDB1 and DDB2, and by XPC-RAD23B complexes.
“In GG-NER, damage is recognized by the DDB (damaged DNA binding protein), involving DDB1 and DDB2, and XPC (Xeroderma pigmentosum complementation group C)-RAD23B complexes [5;6].”
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 [5]
The DDB complex initially recognizes CPD lesions and helps recruit XPC.
“The DDB complex initially recognizes the CPD lesions and helps in recruiting XPC”
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 [5]
6-4PP lesions are directly recognized by XPC independent of DDB.
“whereas 6-4PP lesions are directly recognized by XPC independent of DDB [5–8].”
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 [5]
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 [5]
In GG-NER, UV-DDB (DDB1 and DDB2) and XPC-RAD23B complexes recognize damage.
“In GG-NER, damage is recognized by the UV-DDB (DDB1 and DDB2) and XPC-RAD23B complexes [4, 5].”
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 [4]
The DDB complex first recognizes CPD lesions and recruits XPC, whereas XPC can recognize 6-4PP lesions on its own.
“The DDB complex initially recognizes the CPD lesions and recruits XPC [4, 5, 8, 9], whereas XPC can independently recognize 6-4PP lesions [5].”
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 [4]
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References 34 · Cited by 227
Research works printed but not linked: 3
- [14]14. Hwang, B. J., Ford, J. M., Hanawalt, P. C., and Chu, G. (1999) Proc. Natl. Acad. Sci. U. S. A. 96, 424-428
- [21]21. Wakasugi, M., and Sancar, A. (1998) Proc. Natl. Acad. Sci. U. S. A. 95, 6669-6674
- [22]22. Huang, J. C., Svoboda, D. L., Reardon, J. T., and Sancar, A. (1992) Proc. Natl. Acad. Sci. U. S. A. 89, 3664-3668
- Authors
- Wakasugi, M., Kawashima, A., Morioka, H., Linn, S., Sancar, A., Mori, T., Nikaido, O., & Matsunaga, T.
- Affiliations
- Kanazawa University (JP)
- Hokkaido University (JP)
- University of California, Berkeley (US)
- University of North Carolina at Chapel Hill (US)
- Nara Medical University (JP)
- Corresponding author
- Matsunaga, Tsukasa
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2002-01
- Volume
- 277
- Issue
- 3
- Pages
- 1637-1640
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2028884100
- Cited by
- 227
- References
- 34
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 3 · 2023: 6 · 2022: 6 · 2021: 4 · 2020: 7 · 2019: 6 · 2018: 7 · 2017: 6 · 2016: 9 · 2015: 7 · 2014: 10 · 2013: 7 · 2012: 8
- FWCI
- 7.07
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- University of North Carolina at Chapel Hill
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Carcinogens and Genotoxicity Assessment
- Keywords
- DDB, p48, nucleotide excision repair, UV-induced DNA damage, cyclobutane pyrimidine dimers, 6-4 photoproducts, xeroderma pigmentosum, XPC, XPA, TFIIH, XPG
- MeSH terms
- Cell Line, Transformed, DNA Damage, DNA Repair, DNA-Binding Proteins, Humans, Pyrimidine Dimers, Transfection, Ultraviolet Rays, Xeroderma Pigmentosum Group A Protein
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