Identification of potentially cytotoxic lesions induced by UVA photoactivation of DNA 4-thiothymidine in human cells
Open accessAbstract
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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
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.”
From Photoinduced Damage to Cellular DNA: Direct and Photosensitized Reactions<sup>†</sup> (2012) · cites this paper as [227]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
A simple technique for quantitation of low levels of DNA damage in individual cells
Singh, N. P., McCoy, M. T., Tice, R. R., & Schneider, E. L. (1988) · Experimental Cell Research · doi:10.1016/0014-4827(88)90265-0 · Cited by 10,828 · see citing works
Megabase Chromatin Domains Involved in DNA Double-Strand Breaks in Vivo
Rogakou, E. P., Boon, C., Redon, C., & Bonner, W. M. (1999) · The Journal of Cell Biology · doi:10.1083/jcb.146.5.905 · Cited by 2,422 · see citing works
DNA interstrand crosslink repair and cancer
Deans, A. J., & West, S. C. (2011) · Nature reviews. Cancer · doi:10.1038/nrc3088 · Cited by 1,019 · see citing works
Azathioprine and UVA Light Generate Mutagenic Oxidative DNA Damage
O'Donovan, P., Perrett, C. M., Zhang, X., Montaner, B., Xu, Y., Harwood, C. A., McGregor, J., Walker, S. L., Hanaoka, F., & Karran, P. (2005) · Science · doi:10.1126/science.1114233 · Cited by 631 · see citing works
Self-citationOxidatively generated base damage to cellular DNA
Cadet, J., Douki, T., & Ravanat, J. (2010) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2010.03.025 · Cited by 543 · see citing works
Methods for cultivation of keratinocytes with an air-liquid interface
Pruniéras, M., Régnier, M., & Woodley, D. (1983) · Journal of Investigative Dermatology · doi:10.1111/1523-1747.ep12540324 · Cited by 484 · see citing works
Douki, T., Reynaud-Angelin, A., Cadet, J., & Sage, E. (2003) · Biochemistry · doi:10.1021/bi034593c · Cited by 452 · see citing works
Regulation of human thymidine kinase during the cell cycle.
Sherley, J. L., & Kelly, T. J. (1988) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)68484-4 · Cited by 448 · see citing works
A screening method for isolating DNA repair-deficient mutants of CHO cells
Thompson, L. H., Rubin, J. S., Cleaver, J. E., Whitmore, G. F., & Brookman, K. W. (1980) · Somatic Cell and Molecular Genetics · doi:10.1007/bf01542791 · Cited by 282 · see citing works
A role for ultraviolet A in solar mutagenesis.
Drobetsky, E. A., Turcotte, J., & Châteauneuf, A. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.6.2350 · Cited by 255 · see citing works
Photodynamic therapy in dermatology: state-of-the-art
Babilas, P., Schreml, S., Landthaler, M., & Szeimies, R. (2010) · Photodermatology Photoimmunology & Photomedicine · doi:10.1111/j.1600-0781.2010.00507.x · Cited by 235 · see citing works
Young, A. R., Harrison, G. I., Chadwick, C. A., Nikaido, O., Ramsden, J., & Potten, C. S. (1998) · Journal of Investigative Dermatology · doi:10.1046/j.1523-1747.1998.00436.x · Cited by 235 · see citing works
Self-citationRisk of Squamous Cell Carcinoma and Methoxsalen (Psoralen) and UV-A Radiation (PUVA)
Stern, R. S., & Lunder, E. J. (1998) · Archives of Dermatology · doi:10.1001/archderm.134.12.1582 · Cited by 231 · see citing works
Favre, A., Saintomé, C., Fourrey, J.-L., Clivio, P., & Laugâa, P. (1998) · Journal of Photochemistry and Photobiology B: Biology · doi:10.1016/s1011-1344(97)00116-4 · Cited by 191 · see citing works
Fuller, L. F., & Painter, R. B. (1988) · Mutation Research/DNA Repair Reports · doi:10.1016/0167-8817(88)90041-7 · Cited by 177 · see citing works
T4 Endonuclease Involved in Repair of DNA
Yasuda, S., & Sekiguchi, M. (1970) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.67.4.1839 · Cited by 170 · see citing works
The XRCC2 DNA repair gene from human and mouse encodes a novel member of the recA/RAD51 family
Cartwright, R. (1998) · Nucleic Acids Research · doi:10.1093/nar/26.13.3084 · Cited by 147 · see citing works
UVA1 induces cyclobutane pyrimidine dimers but not 6-4 photoproducts in human skin in vivo
Tewari, A., Sarkany, R. P., & Young, A. R. (2012) · Journal of Investigative Dermatology · doi:10.1038/jid.2011.283 · Cited by 141 · see citing works
Self-citationFayter, D., Corbett, M., Heirs, M. K., Fox, D. C., & Eastwood, A. J. (2010) · Health Technology Assessment · doi:10.3310/hta14370 · Cited by 139 · see citing works
Mutagenic specificity of solar UV light in nucleotide excision repair-deficient rodent cells.
Sage, É., Lamolet, B., Brulay, E., Moustacchi, E., Chteauneuf, A., & Drobetsky, E. A. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.1.176 · Cited by 121 · see citing works
Photoactivation of DNA thiobases as a potential novel therapeutic option
Massey, A. J., Xu, Y., & Karran, P. (2001) · Current Biology · doi:10.1016/s0960-9822(01)00272-x · Cited by 112 · see citing works
Self-citationNovel DNA lesions generated by the interaction between therapeutic thiopurines and UVA light
Zhang, X., Jeffs, G., Ren, X., O’Donovan, P., Montaner, B., Perrett, C. M., Karran, P., & Xu, Y.-Z. (2007) · DNA Repair · doi:10.1016/j.dnarep.2006.11.003 · Cited by 110 · see citing works
Self-citationPhotodynamic Therapy for Urological Malignancies: Past to Current Approaches
Pinthus, J. H., Bogaards, A., Weersink, R., Wilson, B. C., & Trachtenberg, J. (2006) · The Journal of Urology · doi:10.1016/s0022-5347(05)00701-9 · Cited by 109 · see citing works
Temmink, O. H., Emura, T., de Bruin, M., Fukushima, M., & Peters, G. J. (2007) · Cancer Science · doi:10.1111/j.1349-7006.2007.00477.x · Cited by 108 · see citing works
Reactive oxygen‐mediated damage to a human DNA replication and repair protein
Montaner, B., O'Donovan, P., Reelfs, O., Perrett, C. M., Zhang, X., Xu, Y., Ren, X., Macpherson, P., Frith, D., & Karran, P. (2007) · EMBO Reports · doi:10.1038/sj.embor.7401084 · Cited by 88 · see citing works
Self-citationSkin cancers or premalignant lesions occur in half of high-dose PUVA patients
Lever, L. R., & Farr, P. M. (2006) · British Journal of Dermatology · doi:10.1111/j.1365-2133.1994.tb08494.x · Cited by 88 · see citing works
Molecular basis of spontaneous mutation at the aprt locus of hamster cells
Phear, G. A., Armstrong, W., & Meuth, M. (1989) · Journal of Molecular Biology · doi:10.1016/0022-2836(89)90595-0 · Cited by 82 · see citing works
Clivio, P., Fourrey, J., Gasche, J., & Favre, A. (1991) · Journal of the American Chemical Society · doi:10.1021/ja00014a065 · Cited by 76 · see citing works
D'Errico, M., Teson, M., Calcagnile, A., Nardo, T., De Luca, N., Lazzari, C., Soddu, S., Zambruno, G., Stefanini, M., & Dogliotti, E. (2005) · Cancer Research · doi:10.1158/0008-5472.432.65.2 · Cited by 64 · see citing works
Thiothymidine combined with UVA as a potential novel therapy for bladder cancer
Pridgeon, S. W., Heer, R., Taylor, G. A., Newell, D. R., O’Toole, K., Robinson, M., Xu, Y., Karran, P., & Boddy, A. V. (2011) · British Journal of Cancer · doi:10.1038/bjc.2011.180 · Cited by 49 · see citing works
Self-citationCooke, M. S., Duarte, T. L., Cooper, D., Chen, J., Nandagopal, S., & Evans, M. D. (2008) · DNA repair · doi:10.1016/j.dnarep.2008.08.007 · Cited by 48 · see citing works
Efficient DNA interstrand crosslinking by 6-thioguanine and UVA radiation
Brem, R., Daehn, I., & Karran, P. (2011) · DNA Repair · doi:10.1016/j.dnarep.2011.05.010 · Cited by 48 · see citing works
Self-citationSimple synthesis of 4-thiothymidine, 4-thiouridine and 6-thio-2′-deoxyguanosine
Xu, Y., Zheng, Q., & SWANN, P. F. (1991) · Tetrahedron Letters · doi:10.1016/0040-4039(91)85095-m · Cited by 43 · see citing works
Self-citationBrem, R., Li, F., Montaner, B., Reelfs, O., & Karran, P. (2010) · Oncogene · doi:10.1038/onc.2010.140 · Cited by 42 · see citing works
Self-citationPhysical and functional interaction between DDB and XPA in nucleotide excision repair
Wakasugi, M., Kasashima, H., Fukase, Y., Imura, M., Imai, R., Yamada, S., Cleaver, J. E., & Matsunaga, T. (2008) · Nucleic Acids Research · doi:10.1093/nar/gkn964 · Cited by 38 · see citing works
Reelfs, O., Xu, Y.-Z., Massey, A., Karran, P., & Storey, A. (2007) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-07-0166 · Cited by 30 · see citing works
Self-citationGoncalves, O., Drobetsky, E. A., & Meuth, M. (1984) · Molecular and Cellular Biology · doi:10.1128/mcb.4.9.1792 · Cited by 29 · see citing works
Walker, S. L., & Young, A. R. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0703385104 · Cited by 29 · see citing works
Self-citationJones, C. J., CIeaver, J. E., & Wood, R. D. (1992) · Nucleic Acids Research · doi:10.1093/nar/20.5.991 · Cited by 26 · see citing works
Pines, A., Backendorf, C., Alekseev, S., Jansen, J. G., de Gruijl, F. R., Vrieling, H., & Mullenders, L. H. F. (2008) · DNA repair · doi:10.1016/j.dnarep.2008.09.011 · Cited by 25 · see citing works
Thymidine kinase expression. A marker for malignant cells.
Hengstschläger, M., Pfeilstöcker, M., & Wawra, E. (1998) · PubMed · Cited by 23 · see citing works
Hengstschläger, M., Pfeilstöcker, M., & Wawra, E. (1998) · Advances in experimental medicine and biology · doi:10.1007/978-1-4615-5381-6_90 · Cited by 22 · see citing works
Warren, M., Murray, J. B., & Connolly, B. A. (1998) · Journal of Molecular Biology · doi:10.1006/jmbi.1998.1719 · Cited by 22 · see citing works
Clivio, P., Fourrey, J., Gasche, J., et al. (1992) · Tetrahedron Letters · doi:10.1016/s0040-4039(00)91688-5 · Cited by 18 · see citing works
Garcin, G., Douki, T., Stoebner, P., Guesnet, J., Guezennec, A., Martínez, J., Cadet, J., & Meunier, L. (2007) · Photochemical & Photobiological Sciences · doi:10.1039/b615656h · Cited by 13 · see citing works
Goncalves, O., Drobetsky, E. A., & Meuth, M. (1984) · Molecular and Cellular Biology · doi:10.1128/mcb.4.9.1792-1799.1984 · Cited by 5 · see citing works
DNA repair and the cytotoxic effects of cisplatin and DNA thiobases
Massey, A. J. (2001) · OpenGrey (Institut de l'Information Scientifique et Technique) · Cited by 1 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Photoinduced Damage to Cellular DNA: Direct and Photosensitized Reactions<sup>†</sup>
Cadet, J., Mouret, S., Ravanat, J., & Douki, T. (2012) · Photochemistry and Photobiology · doi:10.1111/j.1751-1097.2012.01200.x · Cited by 300 · see citing works
4-thiothymidine sensitization of DNA to UVA offers potential for a novel photochemotherapy
Reelfs, O., Karran, P., & Young, A. R. (2012) · Photochemical & Photobiological Sciences · doi:10.1039/c1pp05188a · Cited by 79 · see citing works
Self-citation
- 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
- Publisher
- Oxford University Press (OUP)
- Published
- 2011-09-02
- Volume
- 39
- Issue
- 22
- Pages
- 9620-9632
- ISSN
- 0305-1048 (ISSN-L)
- 1362-4962
- PMC
- PMC3239200
- 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
- gold
- doi.org
- Licence
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review