Circadian control of XPA and excision repair of cisplatin-DNA damage by cryptochrome and HERC2 ubiquitin ligase
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Cisplatin is one of the most commonly used anticancer drugs. It kills cancer cells by damaging their DNA, and hence cellular DNA repair capacity is an important determinant of its efficacy. Here, we investigated the repair of cisplatin-induced DNA damage in mouse liver and testis tissue extracts prepared at regular intervals over the course of a day. We find that the XPA protein, which plays an essential role in repair of cisplatin damage by nucleotide excision repair, exhibits circadian oscillation in the liver but not in testis. Consequently, removal of cisplatin adducts in liver extracts, but not in testis extracts, exhibits a circadian pattern with zenith at ∼5 pm and nadir at ∼5 am. Furthermore, we find that the circadian oscillation of XPA is achieved both by regulation of transcription by the core circadian clock proteins including cryptochrome and by regulation at the posttranslational level by the HERC2 ubiquitin ligase. These findings may be used as a guide for timing of cisplatin chemotherapy.
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XPA may serve as a potential target for sensitization to cancer chemotherapy (e.g. cisplatin) via manipulation of available nuclear XPA, either at the transcriptional or post-transcriptional level.
“XPA may serve as a potential target for sensitization to cancer chemotherapy (e.g. cisplatin) via manipulation of available nuclear XPA, either at the transcriptional or post-transcriptional level [53], [54], [55].”
From UV-Induced Nuclear Import of XPA Is Mediated by Importin-α4 in An ATR-Dependent Manner (2013) · cites this paper as [53]
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Self-citation
- Authors
- Kang, T.-H., Lindsey-Boltz, L. A., Reardon, J. T., & Sancar, A.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, NC 27599
- Corresponding author
- Sancar, Aziz
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2010-03-16
- Volume
- 107
- Issue
- 11
- Pages
- 4890-4895
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2841896
- OpenAlex
- W2164742545
- Cited by
- 250
- References
- 50
- Citations by year
- 2026: 13 · 2025: 5 · 2024: 11 · 2023: 13 · 2022: 14 · 2021: 16 · 2020: 33 · 2019: 17 · 2018: 14 · 2017: 15 · 2016: 19 · 2015: 12 · 2014: 16 · 2013: 15 · 2012: 16
- FWCI
- 7.43
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- University of Pittsburgh
- National Institutes of Health (GM31082)
- National Institute of General Medical Sciences (R01GM032833, R01GM031082, GM310.82, R37GM031082, GM32833)
- National Institute of Environmental Health Sciences (P30ES010126)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Oncology › Metal complexes synthesis and properties
- Keywords
- circadian clock, XPA, nucleotide excision repair, cisplatin, DNA repair, cryptochrome, post-translational regulation, transcriptional regulation, liver, testis, chemotherapy timing, DNA adducts
- MeSH terms
- Animals, Biological Clocks, Cell Line, Circadian Rhythm, Cisplatin, DNA Damage, DNA Repair, Humans, Liver, Male, Protein Binding, Protein Processing, Post-Translational, RNA, Messenger, Testis, Time Factors, Tissue Extracts, Down-Regulation, DNA Adducts, Guanine Nucleotide Exchange Factors, Ubiquitin-Protein Ligases, Mice, Xeroderma Pigmentosum Group A Protein, Cryptochromes
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