Novel DNA lesions generated by the interaction between therapeutic thiopurines and UVA light
Abstract
The therapeutic effect of the thiopurines, 6-thioguanine (6-TG), 6-mercaptopurine, and its prodrug azathioprine, depends on the incorporation of 6-TG into cellular DNA. Unlike normal DNA bases, 6-TG absorbs UVA radiation, and UVA-mediated photochemical damage of DNA 6-TG has potentially harmful side effects. When free 6-TG is UVA irradiated in solution in the presence of molecular oxygen, reactive oxygen species are generated and 6-TG is oxidized to guanine-6-sulfonate (G(SO3)) and guanine-6-thioguanine in reactions involving singlet oxygen. This conversion is prevented by antioxidants, including the dietary vitamin ascorbate. DNA G(SO3) is also the major photoproduct of 6-TG in DNA and it can be selectively introduced into DNA or oligonucleotides in vitro by mild chemical oxidation. Thermal stability measurements indicate that G(SO3) does not form stable base pairs with any of the normal DNA bases in duplex oligonucleotides and is a powerful block for elongation by Klenow DNA polymerase in primer extension experiments. In cultured human cells, DNA damage produced by 6-TG and UVA treatment is associated with replication inhibition and provokes a p53-dependent DNA damage response.
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Main DNA oxidation products from singlet oxygen oxidation of the thiol function of 6-TG are stable guanine 6-sulphinate and guanine 6-sulfonate via transient guanine 6-sulphenate.
“The main DNA oxidation products arise from 1 O 2 oxidation of the thiol function of 6-TG; they were characterized as stable guanine 6-sulphinate (G S02 ) and guanine 6-sulfonate (G S03 ) through initial transient guanine 6-sulphenate (G SO ) (212,213).”
From Photoinduced Damage to Cellular DNA: Direct and Photosensitized Reactions<sup>†</sup> (2012) · cites this paper as [212]
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- Authors
- Zhang, X., Jeffs, G., Ren, X., O’Donovan, P., Montaner, B., Perrett, C. M., Karran, P., & Xu, Y.-Z.
- Affiliations
- The Open University (GB)
- Cancer Research UK (GB)
- Corresponding author
- Karran, Peter
- Xu, Yao-Zhong
- Venue
- DNA Repair
- Publisher
- Elsevier BV
- Published
- 2007-03-01
- Volume
- 6
- Issue
- 3
- Pages
- 344-354
- ISSN
- 1568-7856 (ISSN-L)
- 1568-7864
- OpenAlex
- W2072173165
- Cited by
- 110
- References
- 28
- Citations by year
- 2026: 2 · 2025: 2 · 2023: 2 · 2022: 4 · 2021: 5 · 2020: 2 · 2019: 5 · 2018: 10 · 2017: 13 · 2016: 8 · 2015: 3 · 2014: 6 · 2013: 3 · 2012: 7
- FWCI
- 2.30
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- DNA repair (publishedVersion)
- PubMed (publishedVersion)
- Open Research Online (The Open University) (submittedVersion)
- Funders
- Royal Society
- Engineering and Physical Sciences Research Council
- 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
- thiopurines, 6-thioguanine, azathioprine, 6-mercaptopurine, DNA photoproducts, singlet oxygen, reactive oxygen species, vitamin C, DNA oxidation, replication inhibition
- MeSH terms
- Antimetabolites, Antineoplastic, Arylsulfonates, DNA, DNA Damage, DNA Replication, Dose-Response Relationship, Radiation, Female, Guanine, Humans, Oxidants, Photochemical, Oxidation-Reduction, Thioguanine, Ultraviolet Rays, Cell Line, Tumor
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