Oxidative stress-induced protein damage inhibits DNA repair and determines mutation risk and therapeutic efficacy
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Abstract
The relationship between sun exposure and nonmelanoma skin cancer risk is well established. Solar UV (wavelength 280–400 nm) is firmly implicated in skin cancer development. Nucleotide excision repair (NER) protects against cancer by removing potentially mutagenic DNA lesions induced by UVB (280–320 nm). How the 20-fold more abundant UVA (320–400 nm) component of solar UV radiation increases skin cancer risk is not understood. Here it is demonstrated that the contribution of UVA to the effect of UV radiation on cultured human cells is largely independent of its ability to damage DNA. Instead, the effects of UVA reflect the induction of oxidative stress that causes extensive protein oxidation. Because NER proteins are among those damaged, UVA irradiation inhibits NER and increases the susceptibility of the cells to mutation by UVB. NER inhibition is a common consequence of oxidative stress. Exposure to chemical oxidants, treatment with drugs that deplete cellular antioxidants, and interventions that interfere with glucose metabolism to disrupt the supply of cellular reducing power all inhibit NER. Tumor cells are often in a condition of oxidative stress and one effect of the NER inhibition that results from stress-induced protein oxidation is an increased sensitivity to the anticancer drug cisplatin. Implications: As NER is both a defense against cancer and a significant determinant of cell survival after treatment with anticancer drugs, its attenuation by protein damage under conditions of oxidative stress has implications for both cancer risk and for the effectiveness of anticancer therapy. Mol Cancer Res; 14(7); 612–22. ©2016 AACR.
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The susceptibility of NER proteins to oxidation generated by UVA or other substances compromises cell protection against DNA damage, with implications for carcinogenesis.
“The susceptibility of the NER proteins to the oxidation generated by UVA or other substances compromises the cell protection against DNA damage, which has clear implications for carcinogenesis [264].”
From Sunlight damage to cellular DNA: focus on oxidatively generated lesions (2017) · cites this paper as [264]
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Cites
Signatures of mutational processes in human cancer
Initiative, A. P. C. G., Alexandrov, L. B., ICGC Breast Cancer Consortium, ICGC MMML-Seq Consortium, PedBrain, I., Nik-Zainal, S., Wedge, D. C., Aparicio, S. A. J. R., Behjati, S., Biankin, A. V., et al. (2013) · Nature · doi:10.1038/nature12477 · Cited by 9,660 · see citing works
Vogelstein, B., Papadopoulos, N., Velculescu, V. E., Zhou, S., Diaz, L. A., & Kinzler, K. W. (2013) · Science · doi:10.1126/science.1235122 · Cited by 7,863 · see citing works
Friedberg, E. C., Walker, G. C., Siede, W., Wood, R. D., Schultz, R. A., & Ellenberger, T. (2005) · doi:10.1128/9781555816704 · Cited by 5,683 · see citing works
The resurgence of platinum-based cancer chemotherapy
Kèlland, L. R. (2007) · Nature reviews. Cancer · doi:10.1038/nrc2167 · Cited by 4,733 · see citing works
High burden and pervasive positive selection of somatic mutations in normal human skin
Martincorena, I., Roshan, A., Gerstung, M., Ellis, P., Van Loo, P., McLaren, S., Wedge, D. C., Fullam, A., Alexandrov, L. B., Tubio, J. M., et al. (2015) · Science · doi:10.1126/science.aaa6806 · Cited by 1,770 · see citing works
Mitochondrial ROS in cancer: initiators, amplifiers or an Achilles' heel?
Sabharwal, S. S., & Schumacker, P. T. (2014) · Nature reviews. Cancer · doi:10.1038/nrc3803 · Cited by 1,643 · see citing works
Ascorbic acid: Chemistry, biology and the treatment of cancer
Du, J., Cullen, J. J., & Buettner, G. R. (2012) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2012.06.003 · Cited by 1,071 · see citing works
Singlet oxygen-mediated damage to proteins and its consequences
Davies, M. J. (2003) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(03)00817-9 · Cited by 996 · see citing works
Oxidative Stress Resistance in<i>Deinococcus radiodurans</i>
Slade, D., & Radman, M. (2011) · Microbiology and Molecular Biology Reviews · doi:10.1128/mmbr.00015-10 · Cited by 761 · see citing works
Mouret, S., Baudouin, C., Charveron, M., Favier, A., Cadet, J., & Douki, T. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0604213103 · Cited by 684 · see citing works
Ma, Y., Chapman, J., Levine, M., Polireddy, K., Drisko, J., & Chen, Q. (2014) · Science Translational Medicine · doi:10.1126/scitranslmed.3007154 · Cited by 501 · see citing works
Oncogenic Isocitrate Dehydrogenase Mutations: Mechanisms, Models, and Clinical Opportunities
Cairns, R. A., & Mak, T. W. (2013) · Cancer Discovery · doi:10.1158/2159-8290.cd-13-0083 · Cited by 452 · see citing works
ATM activates the pentose phosphate pathway promoting anti‐oxidant defence and DNA repair
Cosentino, C., Grieco, D., & Costanzo, V. (2010) · The EMBO Journal · doi:10.1038/emboj.2010.330 · Cited by 436 · see citing works
XERODERMA PIGMENTOSUM: A HUMAN DISEASE IN WHICH AN INITIAL STAGE OF DNA REPAIR IS DEFECTIVE
Cleaver, J. E. (1969) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.63.2.428 · Cited by 409 · see citing works
<scp>UV</scp> Signature Mutations
Brash, D. E. (2015) · Photochemistry and Photobiology · doi:10.1111/php.12377 · Cited by 401 · see citing works
Reactive oxygen species in redox cancer therapy
Tong, L., Chuang, C., Wu, S., & Zuo, L. (2015) · Cancer Letters · doi:10.1016/j.canlet.2015.07.008 · Cited by 394 · see citing works
NOTCH1 Mutations Occur Early during Cutaneous Squamous Cell Carcinogenesis
South, A. P., Purdie, K. J., Watt, S. A., Haldenby, S. T., den Breems, N. Y., Dimon, M. T., Arron, S. T., Kluk, M., Aster, J. C., McHugh, A. T., et al. (2014) · Journal of Investigative Dermatology · doi:10.1038/jid.2014.154 · Cited by 359 · see citing works
Solar and ultraviolet radiation
Gies, P. H., Roy, C., & Udelhofen, P. M. (2004) · Cancer prevention, cancer causes · doi:10.1007/978-94-017-0511-0_3 · Cited by 357 · see citing works
Cadet, J., Douki, T., & Ravanat, J. (2015) · Photochemistry and Photobiology · doi:10.1111/php.12368 · Cited by 355 · see citing works
The Distinctive Mutational Spectra of Polyomavirus-Negative Merkel Cell Carcinoma
Harms, P. W., Vats, P., Verhaegen, M. E., Robinson, D. R., Wu, Y.-M., Dhanasekaran, S. M., Palanisamy, N., Siddiqui, J., Cao, X., Su, F., et al. (2015) · Cancer Research · doi:10.1158/0008-5472.can-15-0702 · Cited by 343 · see citing works
Incidence of skin cancers in 3867 patients treated with narrow-band ultraviolet B phototherapy
Hearn, R., Kerr, A. C., Rahim, K. F., et al. (2008) · British Journal of Dermatology · doi:10.1111/j.1365-2133.2008.08776.x · Cited by 333 · see citing works
Köberle, B., Masters, J. R., Hartley, J. A., & Wood, R. D. (1999) · Current Biology · doi:10.1016/s0960-9822(99)80118-3 · Cited by 298 · see citing works
Temporal Dissection of Tumorigenesis in Primary Cancers
Durinck, S., Ho, C., Wang, N. J., Liao, W. J., Jakkula, L. R., Collisson, E. A., Pons, J., Chan, S.-W., Lam, E. T., Chu, C., et al. (2011) · Cancer Discovery · doi:10.1158/2159-8290.cd-11-0028 · Cited by 267 · see citing works
Mutation assay at the thymidine kinase locus in diploid human lymphoblasts
Liber, H. L., & Thilly, W. G. (1982) · Mutation research. Fundamental and molecular mechanisms of mutagenesis · doi:10.1016/0027-5107(82)90308-6 · Cited by 244 · see citing works
Verrax, J., & Calderón, P. B. (2009) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2009.02.016 · Cited by 232 · see citing works
UVB phototherapy and skin cancer risk: a review of the literature
Lee, E., Koo, J. Y. M., & Berger, T. (2005) · International Journal of Dermatology · doi:10.1111/j.1365-4632.2004.02186.x · Cited by 228 · see citing works
Mutational Landscape of Basal Cell Carcinomas by Whole-Exome Sequencing
Jayaraman, S. S., Rayhan, D. J., Hazany, S., & Kolodney, M. S. (2013) · Journal of Investigative Dermatology · doi:10.1038/jid.2013.276 · Cited by 221 · see citing works
Courdavault, S., Baudouin, C., Charveron, M., Canguilhem, B., Favier, A., Cadet, J., & Douki, T. (2005) · DNA Repair · doi:10.1016/j.dnarep.2005.05.001 · Cited by 156 · see citing works
Oxidation Status of Human OGG1-S326C Polymorphic Variant Determines Cellular DNA Repair Capacity
Bravard, A., Vacher, M., Moritz, E., Vaslin, L., Hall, J. A., Epe, B., & Radicella, J. P. (2009) · Cancer Research · doi:10.1158/0008-5472.can-08-3943 · Cited by 151 · see citing works
Radioprotection of <i>IDH1</i> -Mutated Cancer Cells by the IDH1-Mutant Inhibitor AGI-5198
Molenaar, R. J., Botman, D., Smits, M. A., Hira, V. V., van Lith, S. A., Stap, J., Henneman, P., Khurshed, M., Lenting, K., Mul, A. N., et al. (2015) · Cancer Research · doi:10.1158/0008-5472.can-14-3603 · Cited by 148 · see citing works
Impact of DNA polymorphisms in key DNA base excision repair proteins on cancer risk
Karahalıl, B., Va, B., & Wilson, D. (2012) · Human & Experimental Toxicology · doi:10.1177/0960327112444476 · Cited by 127 · see citing works
PAQR-2 Regulates Fatty Acid Desaturation during Cold Adaptation in C. elegans
Svensk, E., Ståhlman, M., Andersson, C.-H., Johansson, M., Borén, J., & Pilon, M. (2013) · PLoS Genetics · doi:10.1371/journal.pgen.1003801 · Cited by 127 · see citing works
Extreme anti-oxidant protection against ionizing radiation in bdelloid rotifers
Krisko, A., Leroy, M., Radman, M., & Meselson, M. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1119762109 · Cited by 121 · see citing works
Enninga, I. C., Groenendijk, R. T. L., Filon, A. R., van Zeeland, A. A., & Simons, J. W. I. M. (1986) · Carcinogenesis · doi:10.1093/carcin/7.11.1829 · Cited by 109 · see citing works
Smith, P. J., & Paterson, M. C. (1982) · Photochemistry and Photobiology · doi:10.1111/j.1751-1097.1982.tb04383.x · Cited by 83 · see citing works
Reduced dimer excision in bacteria following near ultraviolet (365 nm) radiation
Tyrrell, R. M., & Webb, R. B. (1973) · Mutation research. Fundamental and molecular mechanisms of mutagenesis · doi:10.1016/0027-5107(73)90238-8 · Cited by 82 · see citing works
Phenotypic and Genetic Consequences of Protein Damage
Kriško, A., & Radman, M. (2013) · PLoS Genetics · doi:10.1371/journal.pgen.1003810 · Cited by 63 · see citing works
Oxidative damage to RPA limits the nucleotide excision repair capacity of human cells
Guven, M., Brem, R., Macpherson, P., Peacock, M., & Karran, P. (2015) · Journal of Investigative Dermatology · doi:10.1038/jid.2015.255 · Cited by 61 · see citing works
Self-citationProtein Oxidation and DNA Repair Inhibition by 6-Thioguanine and UVA Radiation
Guéranger, Q., Li, F., Peacock, M., Larnicol, A., Brem, R., Macpherson, P., Egly, J., & Karran, P. (2013) · Journal of Investigative Dermatology · doi:10.1038/jid.2013.509 · Cited by 54 · see citing works
Self-citationAyene, I. S., Stamato, T. D., Mauldin, S. K., Biaglow, J. E., Tuttle, S. W., Jenkins, S. F., & Koch, C. J. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m111366200 · Cited by 49 · see citing works
The Risk of Skin Cancer in Psoriasis Patients Treated with UVB Therapy
Osmančević, A., Gillstedt, M., Wennberg, A., et al. (2014) · Acta Dermato Venereologica · doi:10.2340/00015555-1753 · Cited by 39 · see citing works
Mutant IDH1 is required for IDH1 mutated tumor cell growth
Jin, G., Pirozzi, C. J., Chen, L. H., Lopez, G. Y., Duncan, C. G., Feng, J., Spasojević, I., Bigner, D. D., He, Y., & Yan, H. (2012) · Oncotarget · doi:10.18632/oncotarget.577 · Cited by 35 · see citing works
TFIIH Enzymatic Activities in Transcription and Nucleotide Excision Repair
Lainé, J., Mocquet, V., & Egly, J. (2006) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(06)08015-3 · Cited by 33 · see citing works
Brinkmeyer, M. K., & David, S. S. (2015) · DNA repair · doi:10.1016/j.dnarep.2015.08.001 · Cited by 31 · see citing works
INHIBITION OF DNA REPAIR SYNTHESIS BY SUNLIGHT
Parsons, P. G., & Hayward, I. P. (1985) · Photochemistry and Photobiology · doi:10.1111/j.1751-1097.1985.tb08944.x · Cited by 30 · see citing works
Ferguson, B. E., & Oh, D. H. (2005) · Cancer Research · doi:10.1158/0008-5472.can-05-1457 · Cited by 30 · see citing works
Yagi, Y., Ogawara, D., Iwai, S., Hanaoka, F., Akiyama, M., & Maki, H. (2005) · DNA repair · doi:10.1016/j.dnarep.2005.06.010 · Cited by 28 · see citing works
DNA repair inhibition by UVA photoactivated fluoroquinolones and vemurafenib
Peacock, M., Brem, R., Macpherson, P., & Karran, P. (2014) · Nucleic Acids Research · doi:10.1093/nar/gku1213 · Cited by 24 · see citing works
Self-citationRedox‐dependent formation of disulfide bonds in human replication protein A
Men, L., Roginskaya, M., Zou, Y., & Wang, Y. (2007) · Rapid Communications in Mass Spectrometry · doi:10.1002/rcm.3144 · Cited by 18 · see citing works
Holmberg, M. (1983) · Photochemistry and Photobiology · doi:10.1111/j.1751-1097.1983.tb04475.x · Cited by 10 · see citing works
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Sunscreen photoprotection and vitamin D status
Passeron, T., Bouillon, R., Callender, V., Cestari, T., Diepgen, T. L., Green, A. C., van der Pols, J. C., Bernard, B. A., Ly, F., Bernerd, F., et al. (2019) · British Journal of Dermatology · doi:10.1111/bjd.17992 · Cited by 200 · see citing works
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Lawrence, K. P., Long, P. F., & Young, A. R. (2019) · Current Medicinal Chemistry · doi:10.2174/0929867324666170529124237 · Cited by 157 · see citing works
Lawrence, K. P., Douki, T., Sarkany, R. P. E., Acker, S., Herzog, B., & Young, A. R. (2018) · Scientific Reports · doi:10.1038/s41598-018-30738-6 · Cited by 143 · see citing works
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- Authors
- McAdam, E., Brem, R., & Karran, P.
- Affiliations
- The Francis Crick Institute (GB)
- Corresponding author
- Karran, Peter
- ORCID
- Brem, Reto
- Venue
- Molecular Cancer Research
- Published
- 2016-07-01
- Volume
- 14
- Issue
- 7
- Pages
- 612-622
- ISSN
- 1541-7786 (ISSN-L)
- 1557-3125
- PMC
- PMC4955916
- OpenAlex
- W2341278327
- Cited by
- 86
- References
- 50
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 6 · 2023: 8 · 2022: 10 · 2021: 13 · 2020: 13 · 2019: 9 · 2018: 6 · 2017: 6 · 2016: 7
- FWCI
- 4.85
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Figshare (submittedVersion, cc-by)
- Funders
- Francis Crick Institute (10098)
- Cancer Research UK (A3558, 11584, A11584)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Dermatology › Skin Protection and Aging
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Effects of Radiation Exposure
- Keywords
- oxidative stress, protein oxidation, nucleotide excision repair, UVA, UV-B radiation, non-melanoma skin cancer, DNA repair inhibition, cisplatin sensitivity, reducing power, glucose metabolism, anticancer drug efficacy
- MeSH terms
- DNA Damage, DNA Repair, HeLa Cells, Humans, Mutation, Risk Factors, Ultraviolet Rays, Keratinocytes, Mutagenesis, Reactive Oxygen Species, Oxidative Stress, Cell Line, Tumor
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