Cited by 36Photodynamic Therapy Research StudiesDNA Repair MechanismsDNA and Nucleic Acid Chemistry

Identification of potentially cytotoxic lesions induced by UVA photoactivation of DNA 4-thiothymidine in human cells

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Reelfs, Olivier, Macpherson, Peter, Ren, Xiaolin, Xu, Yao-Zhong, Karran, Peter, Young, Antony R.·2011·Nucleic Acids Research

Abstract

Photochemotherapy-in which a photosensitizing drug is combined with ultraviolet or visible radiation-has proven therapeutic effectiveness. Existing approaches have drawbacks, however, and there is a clinical need to develop alternatives offering improved target cell selectivity. DNA substitution by 4-thiothymidine (S(4)TdR) sensitizes cells to killing by ultraviolet A (UVA) radiation. Here, we demonstrate that UVA photoactivation of DNA S(4)TdR does not generate reactive oxygen or cause direct DNA breakage and is only minimally mutagenic. In an organotypic human skin model, UVA penetration is sufficiently robust to kill S(4)TdR-photosensitized epidermal cells. We have investigated the DNA lesions responsible for toxicity. Although thymidine is the predominant UVA photoproduct of S(4)TdR in dilute solution, more complex lesions are formed when S(4)TdR-containing oligonucleotides are irradiated. One of these, a thietane/S(5)-(6-4)T:T, is structurally related to the (6-4) pyrimidine:pyrimidone [(6-4) Py:Py] photoproducts induced by UVB/C radiation. These lesions are detectable in DNA from S(4)TdR/UVA-treated cells and are excised from DNA more efficiently by keratinocytes than by leukaemia cells. UVA irradiation also induces DNA interstrand crosslinking of S(4)TdR-containing duplex oligonucleotides. Cells defective in repairing (6-4) Py:Py DNA adducts or processing DNA crosslinks are extremely sensitive to S(4)TdR/UVA indicating that these lesions contribute significantly to S(4)TdR/UVA cytotoxicity.

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  • High phototoxicity is rationalized by oxygen-independent formation of DNA photoproducts including S5 thietane derivative, a 6-4PP analogue, through photocycloaddition with vicinal thymine and putative ICLs.

    “This was rationalized in terms of oxygenindependent formation of DNA photoproducts including an expected S5 thietane derivative, a 6-4PP analogue (227), through photocycloaddition with vicinal thymine and putative ICLs (228) that however remain to be characterized.”

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Authors
Reelfs, O., Macpherson, P., Ren, X., Xu, Y.-Z., Karran, P., & Young, A. R.
Affiliations
King's College London (GB)
Corresponding author
Reelfs, Olivier
Venue
Nucleic Acids Research
Published
2011-09-02
Volume
39
Issue
22
Pages
9620-9632
ISSN
  • 0305-1048 (ISSN-L)
  • 1362-4962
OpenAlex
W2104094507
Cited by
36
References
47
Citations by year
2025: 4 · 2024: 2 · 2020: 4 · 2019: 2 · 2018: 4 · 2017: 1 · 2016: 7 · 2015: 3 · 2014: 4 · 2013: 2 · 2012: 2
FWCI
2.45
Type
journal article
Language
en
Open access
Locations
  • Nucleic Acids Research (publishedVersion, cc-by-nc)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • Open Research Online (The Open University) (acceptedVersion)
  • Research Portal (King's College London) (submittedVersion)
Funders
  • King's College Hospital NHS Foundation Trust
  • Cancer Research UK (11584)
  • National Institute for Health and Care Research
  • British Skin Foundation
  • King's College London
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Photodynamic Therapy Research Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
Keywords
4-thiothymidine, photochemotherapy, DNA photoproducts, DNA interstrand cross-linking, DNA repair, keratinocytes, leukemia cells, organotypic skin model, cytotoxicity, reactive oxygen species, mutagenicity
MeSH terms
Animals, Cell Line, DNA, DNA Damage, DNA Repair, Cricetinae, Humans, Oligonucleotides, Pyrimidine Dimers, Skin, Thymidine, Ultraviolet Rays, Mutagenesis, Reactive Oxygen Species

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