Recruitment of DNA damage checkpoint proteins to damage in transcribed and nontranscribed sequences
Open accessAbstract
We developed a chromatin immunoprecipitation method for analyzing the binding of repair and checkpoint proteins to DNA base lesions in any region of the human genome. Using this method, we investigated the recruitment of DNA damage checkpoint proteins RPA, Rad9, and ATR to base damage induced by UV and acetoxyacetylaminofluorene in transcribed and nontranscribed regions in wild-type and excision repair-deficient human cells in G1 and S phases of the cell cycle. We find that all 3 damage sensors tested assemble at the site or in the vicinity of damage in the absence of DNA replication or repair and that transcription enhances recruitment of checkpoint proteins to the damage site. Furthermore, we find that UV irradiation of human cells defective in excision repair leads to phosphorylation of Chk1 kinase in both G1 and S phase of the cell cycle, suggesting that primary DNA lesions as well as stalled transcription complexes may act as signals to initiate the DNA damage checkpoint response.
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Jiang and Sancar showed that ATR binds damaged DNA directly without lesion processing.
“Jiang and Sancar showed direct binding of ATR to the damaged DNA without lesion processing, raising the possibility that ATR may activate the checkpoint signaling directly [30].”
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 [30]
Outside S phase and in non-cycling cells, UV lesions alone cannot activate the checkpoint; NER plays a major role in triggering the checkpoint response, though contrasting results exist.
“Outside of S phase and in non cycling cells the situation is quite different. Recent analysis showed that UV lesions themselves cannot activate the checkpoint and NER plays a major role in triggering the checkpoint response, although contrasting results have also been reported [52–57].”
From Mind the gap: keeping UV lesions in check (2011) · cites this paper as [52]
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“Jiang and Sancar showed direct binding of ATR to the damaged DNA without lesion processing, raising the possibility that ATR may activate the checkpoint signaling directly [30].”
BackgroundBomgarden, R. D., Lupardus, P. J., Soni, D. V., Yee, M., Ford, J. M., & Cimprich, K. A. (2006) · The EMBO Journal · doi:10.1038/sj.emboj.7601123 · Cited by 87 · see citing works
RETRACTED: PKA-Mediated Phosphorylation of ATR Promotes Recruitment of XPA to UV-Induced DNA Damage
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RetractedReconstitution of a human ATR-mediated checkpoint response to damaged DNA.
Choi, J.-H., Lindsey-Boltz, L. A., & Sancar, A. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0706013104 · Cited by 64 · see citing works
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The human ATR-mediated DNA damage checkpoint in a reconstituted system
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Self-citationRetracted: AKAP12 mediates PKA-induced phosphorylation of ATR to enhance nucleotide excision repair
Jarrett, S. G., Wolf Horrell, E. M., & D'Orazio, J. A. (2016) · Nucleic Acids Research · doi:10.1093/nar/gkw871 · Cited by 23 · see citing works
RetractedJarrett, S. G., Carter, K. M., Shelton, B. J., & D’Orazio, J. A. (2017) · Scientific Reports · doi:10.1038/s41598-017-12056-5 · Cited by 13 · see citing works
Retracted
- Authors
- Jiang, G., & Sancar, A.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Sancar, Aziz
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2006-01
- Volume
- 26
- Issue
- 1
- Pages
- 39-49
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC1317637
- OpenAlex
- W2162891049
- Cited by
- 70
- References
- 61
- Citations by year
- 2026: 1 · 2024: 1 · 2022: 1 · 2021: 3 · 2020: 2 · 2019: 2 · 2018: 6 · 2017: 5 · 2016: 5 · 2015: 3 · 2014: 3 · 2013: 6 · 2012: 1
- FWCI
- 2.02
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- National Institutes of Health
- 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 › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Keywords
- DNA damage checkpoint, RPA, Rad9, ATR, Chk1 phosphorylation, UV-induced DNA damage, base damage, transcription, transcribed regions, DNA repair, cell cycle, chromatin immunoprecipitation
- MeSH terms
- Checkpoint Kinase 1, Cell Cycle, Cells, Cultured, DNA, DNA Damage, DNA Repair, Dose-Response Relationship, Radiation, Humans, Phosphorylation, Protein Kinases, Transcription, Genetic, Ultraviolet Rays, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Chromatin Immunoprecipitation, Replication Protein A, Ataxia Telangiectasia Mutated Proteins
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