Widespread atypical UV-induced mutations form in single-stranded DNA
Year: 2026
Type: article
Abstract: Persistence of common ultraviolet (UV)–induced lesions, like cyclobutane pyrimidine dimers (CPDs) and pyrimidine-pyrimidone (6-4) photoproducts (6-4-PPs), typically results in C>T substitutions at dipyrimidines: a mutation pattern that composes the single-base substitution (SBS) signature 7 in cancer. Oncogenic melanoma mutations rarely involve SBS7-like substitutions. We recently identified noncanonical UV-induced mutations in yeast that appear to originate from atypical AC and TA photoproducts. While an AC photoproduct could account for formation of BRAF V600K, other melanoma drivers like BRAF V600E and NRAS Q61K involve other mutation types, suggesting possible existence of additional atypical photoproducts. Here, we couple temperature-induced telomeric end resection in yeast with serial UV irradiation and whole-genome sequencing to show UV light induces an extended array of noncanonical mutations in single-stranded DNA (ssDNA). This includes AT>AM, GT>GV, AC>AA, AT>TT, and TA>TT substitutions that are resistant to photo-reversion, indicating that they likely originate from atypical photoproducts. UV-induced mutation spectra in yeast lacking Rad30 indicated that Pol η plays substantial roles in the bypass of CPDs and 6-4-PPs regardless of telomere proximity. Unexpectedly, expression of a mutant DNA pol ε (pol2 M644G) reduced both canonical and noncanonical UV-induced mutations specifically within subtelomeric regions of the genome. This suggests a preferential role for pol ε in the resynthesis of uncapped telomeres, with the M644G mutation conferring accurate lesion bypass capabilities to the replicative polymerase. ssDNA-specific UV lesions provide additional damage-mediated mechanisms for the production of oncogenic mutations in melanoma, such as the BRAF V600E mutation that involves a GT>GA substitution.
Source: UNC Libraries
DOI: 10.17615/k9zn-sf48
Institution: University of North Carolina at Chapel Hill
Language: English
Topic: DNA Repair Mechanisms
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funders: Hevolution Foundation, Support for Pioneering Research Initiated by the Next Generation, Bill and Melinda Gates Foundation, Alfred P. Sloan Foundation, Simons Foundation, American Heart Association, Kavli Foundation, Milton and Tamar Maltz Family Foundation, American Foundation for Aging Research, California Department of Pesticide Regulation, UNICEF, Northwestern University, Natural Science Foundation of Shanghai, Naito Foundation, Takeda Science Foundation, City University of Hong Kong, Texas A and M University, Pennsylvania State University, McGill University, Joachim Herz Stiftung, Uehara Memorial Foundation, Berthold Leibinger Stiftung, Ludwig Institute for Cancer Research, Wellcome Trust, Allegheny Health Network, Compute Canada, Génome Québec, Simons Foundation Autism Research Initiative, Ministerio de Ciencia, Innovación y Universidades, Royal Free London NHS Foundation Trust, Key Laboratory in Science and Technology Development Project of Suzhou, J. Gustaf Richert Stiftelse, Natural Science Foundation of Shenzhen City, Ho Chi Minh City University of Technology and Education, Jiangsu Commission of Health, Leverhulme Trust, Royal Society, University of Leeds, European Commission, National Research Foundation Singapore, Nanyang Technological University, Department of Atomic Energy, Government of India, Robert Bosch Stiftung, Deutsche Forschungsgemeinschaft, International Brain Research Organization, University of Sydney, Canada Research Chairs, Fundação de Amparo à Pesquisa do Estado de São Paulo, National Natural Science Foundation of China, ZonMw, Fundacja na rzecz Nauki Polskiej, AXA Research Fund, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Bundesministerium für Bildung und Forschung, Sun Yat-sen University, Fonds De La Recherche Scientifique - FNRS, China Postdoctoral Science Foundation, Fédération Wallonie-Bruxelles, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Natural Science Foundation of Fujian Province, Science and Technology Commission of Shanghai Municipality, Ministerium für Wissenschaft, Forschung und Kunst Baden-Württemberg, Conselho Nacional de Desenvolvimento Científico e Tecnológico, National Rehabilitation Center, National Research Foundation of Korea, Department of Health, State Government of Victoria, Ilam University of Medical Sciences, Narodowe Centrum Nauki, Vetenskapsrådet, Terry Fox Research Institute, Bundesministerium für Forschung und Technologie, Chinese Academy of Medical Sciences, Kermanshah University of Medical Sciences, Anhui University of Technology, Ardabil University of Medical Sciences, Natural Science Foundation of Shandong Province, NOMIS Stiftung, Region Skåne, Sveaskog, Science, Technology and Innovation Commission of Shenzhen Municipality, Natural Science Foundation Project of Chongqing, Chongqing Science and Technology Commission, Ministry of Science and ICT, South Korea, Business Finland, Consortium of International Agricultural Research Centers, Fonds Spéciaux de Recherche, William Buckland Foundation, National Institutes of Health, Defense Threat Reduction Agency, National Institute of Food and Agriculture, Multidisciplinary University Research Initiative, Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada, Fonds de Recherche du Québec - Santé, Engineering and Physical Sciences Research Council, Biotechnology and Biological Sciences Research Council, Australian Research Council, National Health and Medical Research Council, RIKEN, European Regional Development Fund, Agencia Estatal de Investigación, National Key Research and Development Program of China, Fundamental Research Funds for the Central Universities, Science and Technology Planning Project of Guangdong Province, Lady Davis Institute for Medical Research, Science and Technology Innovation Plan Of Shanghai Science and Technology Commission, Basic and Applied Basic Research Foundation of Guangdong Province, National Institute on Aging, National Heart, Lung, and Blood Institute, NIH Office of the Director, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, EPSRC Centre for Doctoral Training in Medical Imaging, Exploratory Research for Advanced Technology, DEVCOM Army Research Laboratory, Natural Science Foundation of Zhejiang Province, Wellcome Leap, Hong Kong Jockey Club
OpenAlex ID: W7213581290