Efficient DNA interstrand crosslinking by 6-thioguanine and UVA radiation
Abstract
Patients taking the immunosuppressant and anticancer thiopurines 6-mercaptopurine, azathioprine or 6-thioguanine (6-TG), develop skin cancer at a very high frequency. Their DNA contains 6-TG which absorbs ultraviolet A (UVA) radiation, and their skin is UVA hypersensitive, consistent with the formation of DNA photodamage. Here we demonstrate that UVA irradiation of 6-TG-containing DNA causes DNA interstrand crosslinking. In synthetic duplex oligodeoxynucleotides, the interstrand crosslinks (ICLs) can form between closely opposed 6-TG bases and, in a less favoured reaction, between 6-TG and normal bases on the opposite strand. In vivo, UVA irradiation of cultured cells containing 6-TG-substituted DNA also causes ICL formation and induces the chromosome aberrations that are characteristically associated with this type of DNA lesion. 6-TG/UVA activates the Fanconi anemia (FA) pathway via monoubiquitination of the FANCD2 protein. Cells defective in the FA pathway or other factors involved in ICL processing, such as XPF and DNA Polζ, are all hypersensitive to killing by 6-TG/UVA-consistent with a significant contribution of photochemical ICLs to the cytotoxicity of this treatment. Our findings suggest that sunlight-exposed skin of thiopurine treated patients may experience chronic photochemical DNA damage that requires constant intervention of the FA pathway.
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6-TG-photosensitized formation of DPCs and DNA ICLs was observed in model compounds and CCRF-CEM leukemia cells.
“The formation of two other main classes of 6-TG-photosensitized photoproducts, including DPCs and DNA ICLs, was also observed in model compounds and CCRF-CEM leukemia cells (214,215).”
From Photoinduced Damage to Cellular DNA: Direct and Photosensitized Reactions<sup>†</sup> (2012) · cites this paper as [215]
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- Authors
- Brem, R., Daehn, I., & Karran, P.
- Affiliations
- Cancer Research UK (GB)
- Corresponding author
- Karran, Peter
- Venue
- DNA Repair
- Publisher
- Elsevier BV
- Published
- 2011-08
- Volume
- 10
- Issue
- 8
- Pages
- 869-876
- ISSN
- 1568-7856 (ISSN-L)
- 1568-7864
- OpenAlex
- W2032279256
- Cited by
- 48
- References
- 33
- Citations by year
- 2025: 2 · 2024: 2 · 2023: 2 · 2022: 3 · 2021: 5 · 2020: 1 · 2019: 2 · 2018: 3 · 2017: 5 · 2016: 6 · 2015: 1 · 2014: 3 · 2013: 6 · 2012: 4
- FWCI
- 2.08
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- DNA repair (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Cancer Research UK
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Carcinogens and Genotoxicity Assessment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Keywords
- 6-thioguanine, UVA, DNA interstrand cross-linking, thiopurines, Fanconi anemia pathway, FANCD2 monoubiquitination, XPD, chromosomal abnormalities, skin cancer, DNA photodamage
- MeSH terms
- Animals, Cell Survival, Chromosome Aberrations, Cross-Linking Reagents, DNA Repair, Fanconi Anemia, Fibroblasts, Humans, Polydeoxyribonucleotides, Thioguanine, Ultraviolet Rays, Genomic Instability, Cell Line, Tumor, Mice
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