Cited by 110DNA Repair MechanismsCarcinogens and Genotoxicity AssessmentDNA and Nucleic Acid Chemistry

Novel DNA lesions generated by the interaction between therapeutic thiopurines and UVA light

Zhang, Xiaohong, Jeffs, Graham, Ren, Xiaolin, O’Donovan, Peter, Montaner, Beatriz, Perrett, Conal M., Karran, Peter, Xu, Yao-Zhong·2007·DNA Repair

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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Crossref · 10.1016/j.dnarep.2006.11.003

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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).”

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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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