Differential DNA lesion formation and repair in heterochromatin and euchromatin
Open accessAbstract
Discretely orchestrated chromatin condensation is important for chromosome protection from DNA damage. However, it is still unclear how different chromatin states affect the formation and repair of nucleotide excision repair (NER) substrates, e.g. ultraviolet (UV)-induced cyclobutane pyrimidine dimers (CPD) and the pyrimidine (6-4) pyrimidone photoproducts (6-4PP), as well as cisplatin-induced intrastrand crosslinks (Pt-GG). Here, by using immunofluorescence and chromatin immunoprecipitation assays, we have demonstrated that CPD, which cause minor distortion of DNA double helix, can be detected in both euchromatic and heterochromatic regions, while 6-4PP and Pt-GG, which cause major distortion of DNA helix, can exclusively be detected in euchromatin, indicating that the condensed chromatin environment specifically interferes with the formation of these DNA lesions. Mechanistic investigation revealed that the class III histone deacetylase SIRT1 is responsible for restricting the formation of 6-4PP and Pt-GG in cells, probably by facilitating the maintenance of highly condensed heterochromatin. In addition, we also showed that the repair of CPD in heterochromatin is slower than that in euchromatin, and DNA damage binding protein 2 (DDB2) can promote the removal of CPD from heterochromatic region. In summary, our data provide evidence for differential formation and repair of DNA lesions that are substrates of NER. Both the sensitivity of DNA to damage and the kinetics of repair can be affected by the underlying level of chromatin compaction.
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DNA condensation state affects formation of pyrimidine dimers: CPDs can be formed in both hetero and euchromatin regions, whereas 6-4PPs are uniquely formed in euchromatin.
“The DNA condensation state also affects the formation of these pyrimidine dimers: specifically, CPDs can be formed in both hetero and euchromatin regions, whereas 6-4PPs are uniquely formed in euchromatin [36].”
From Sunlight damage to cellular DNA: focus on oxidatively generated lesions (2017) · cites this paper as [36]
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Theoretical approach of complex DNA lesions : from formation to repair
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- Authors
- Han, C., Srivastava, A. K., Cui, T., Wang, Q.-E., & Wani, A. A.
- Affiliations
- The Ohio State University Wexner Medical Center (US)
- The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (US)
- Corresponding author
- Wang, Qi-En
- Wani, Altaf A.
- Venue
- Carcinogenesis
- Publisher
- Oxford University Press (OUP)
- Published
- 2015-12-30
- Volume
- 37
- Issue
- 2
- Pages
- 129-138
- ISSN
- 0143-3334 (ISSN-L)
- 1460-2180
- PMC
- PMC5006209
- OpenAlex
- W2261190630
- Cited by
- 58
- References
- 45
- Citations by year
- 2026: 1 · 2025: 9 · 2024: 3 · 2023: 3 · 2022: 3 · 2021: 9 · 2020: 6 · 2019: 10 · 2018: 3 · 2017: 7 · 2016: 4
- FWCI
- 2.02
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Carcinogenesis (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (R01CA151248, CA151248)
- National Institute of Environmental Health Sciences (ES012991, R01ES002388, R01ES012991, ES002388)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
- Keywords
- nucleotide excision repair, heterochromatin, euchromatin, chromatin condensation, cyclobutane pyrimidine dimers, 6-4 pyrimidone photoproducts, SIRT1, histone deacetylase, DDB2, UV-induced DNA damage
- MeSH terms
- Cells, Cultured, DNA Damage, DNA Repair, Fluorescent Antibody Technique, Heterochromatin, Humans, Pyrimidine Dimers, Immunoblotting, Euchromatin, RNA Interference, Chromatin Immunoprecipitation
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