Reactive oxygen species generated by thiopurine/UVA cause irreparable transcription-blocking DNA lesions
Open accessAbstract
Long-term treatment with the anticancer and immunosuppressant thiopurines, azathioprine or 6-mercaptopurine, is associated with acute skin sensitivity to ultraviolet A (UVA) radiation and a high risk of skin cancer. 6-thioguanine (6-TG) that accumulates in the DNA of thiopurine-treated patients interacts with UVA to generate reactive oxygen species. These cause lethal and mutagenic DNA damage. Here we show that the UVA/DNA 6-TG interaction rapidly, and essentially irreversibly, inhibits transcription in cultured human cells and provokes polyubiquitylation of the major subunit of RNA polymerase II (RNAPII). In vitro, 6-TG photoproducts, including the previously characterized guanine-6-sulfonate, in the transcribed DNA strand, are potent blocks to RNAPII transcription whereas 6-TG is only slightly inhibitory. In vivo, guanine-6-sulfonate is removed poorly from DNA and persists to a similar extent in the DNA of nucleotide excision repair-proficient and defective cells. Furthermore, transcription coupled repair-deficient Cockayne syndrome cells are not hypersensitive to UVA/6-TG, indicating that potentially lethal photoproducts are not selectively excised from transcribed DNA. Since persistent transcription-blocking DNA lesions are associated with acute skin responses to sunlight and the development of skin cancer, our findings have implications for skin cancer in patients undergoing thiopurine therapy.
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UVA activation of thiopurines causes inhibition of transcription and abrogation of cell-cycle checkpoints in cultured human cells through generation of DNA damage.
“An indication for the induction of the deleterious effects triggered by UVA activation of thiopurines was provided indirectly by the observed inhibition of transcription (207) and abrogation of cell-cycle checkpoints (208) in cultured human cells treated with thiopurine and UVA radiation through the generation of DNA damage.”
From Photoinduced Damage to Cellular DNA: Direct and Photosensitized Reactions<sup>†</sup> (2012) · cites this paper as [207]
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- Authors
- Brem, R., Li, F., & Karran, P.
- Affiliations
- Cancer Research UK (GB)
- Corresponding author
- Karran, P.
- Venue
- Nucleic Acids Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2009-01-21
- Volume
- 37
- Issue
- 6
- Pages
- 1951-1961
- ISSN
- 0305-1048 (ISSN-L)
- 1362-4962
- PMC
- PMC2665240
- OpenAlex
- W2087624153
- Cited by
- 67
- References
- 33
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 1 · 2023: 2 · 2022: 2 · 2021: 2 · 2020: 4 · 2019: 2 · 2018: 6 · 2017: 5 · 2016: 5 · 2015: 3 · 2014: 2 · 2013: 4 · 2012: 4
- FWCI
- 3.09
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Nucleic Acids Research (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- Cancer Research UK
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Dermatology › Skin Protection and Aging
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Carcinogens and Genotoxicity Assessment
- Keywords
- thiopurines, 6-thioguanine, UVA, reactive oxygen species, transcription inhibition, RNA polymerase II, DNA lesions, nucleotide excision repair, Cockayne syndrome, skin cancer, azathioprine, 6-mercaptopurine
- MeSH terms
- Antimetabolites, Antineoplastic, Cell Line, DNA, DNA Damage, DNA Repair, Humans, RNA Polymerase II, Thioguanine, Transcription, Genetic, Ultraviolet Rays, Reactive Oxygen Species
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