Differential roles of Rad18 in repressing carcinogen- and oncogene-driven mutagenesis in vivo
Year: 2026
Type: article
Abstract: ABSTRACT The DNA repair protein RAD18 activates ‘Y-family’ Trans-Lesion Synthesis (TLS) DNA polymerases that are DNA damage-tolerant and potentially error-prone. RAD18 is also frequently overexpressed and pathologically activated in cancer cells. However, the extent to which RAD18 shapes cancer genomes and impacts tumorigenesis is unclear. Therefore, we tested the effect of Rad18 status on chemically-induced and oncogene-driven tumorigenesis. In a chemically-induced oral carcinogenesis model, acute (2-16 days) 4NQO-treatment induces expression of Rad18 and TLS polymerase mRNAs in mouse oral epithelial cells prior to emergence of oral squamous cell carcinomas (OSCCs). Chronic (8 week) 4NQO-treatment leads to onset of oral tumors that is accelerated in Rad18 -/- mice when compared with Rad18 +/+ animals. Analysis of OSCC exomes reveals increased levels of G(C)>T(A) transversions in Rad18 -/- tumors when compared with Rad18 +/+ . Therefore, Rad18 promotes error-free bypass of 4NQO-induced DNA lesions and suppresses 4NQO-induced oral carcinogenesis. In a Kras G12D -induced lung carcinogenesis model, Rad18 -deficiency did not affect rates or incidence of oncogene-induced lung tumors or mutations. Taken together, we demonstrate that Rad18 has context-specific tumor-suppressive activity. Given the prevalence of 4NQO-like environmental exposures, RAD18 is highly likely to shape human cancer genomes and perhaps influence other aspects of the tumorigenic process.
Source: NAR Cancer
Language: English
Topic: DNA Repair Mechanisms
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,583
Funders: Remondi Family Foundation, Brain and Behavior Research Foundation, Alzheimer's Association, Alzheimer's Drug Discovery Foundation, University of Southern California, George Washington University, North Carolina State University, University of Victoria, Eastern Health Foundation, Northern California Institute for Research and Education, Veloxis Pharmaceuticals, Australian Government, International Coral Reef Society, Alzheimer's Society, ResMed, San Antonio Medical Foundation, National Institute for Health and Care Research, Leverhulme Trust, Japan Society for the Promotion of Science London, Natural History Museum, Deutsche Forschungsgemeinschaft, Japan Science and Technology Corporation, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Fundação de Amparo à Pesquisa do Estado de São Paulo, National Natural Science Foundation of China, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Bundesministerium für Bildung und Forschung, Inje University, Cooperative Research Centres, Australian Government Department of Industry, Shanxi Scholarship Council of China, Conselho Nacional de Desenvolvimento Científico e Tecnológico, Korea Health Industry Development Institute, National Research Foundation of Korea, Khon Kaen University, Natural Science Foundation of Shanxi Province, Lietuvos Mokslo Taryba, Fundação de Amparo à Pesquisa do Estado de Minas Gerais, Fundação de Amparo à Pesquisa do Estado de Goiás, Medizinische Universität Wien, Shanxi Medical University, Universität Leipzig, Bayerisches Staatsministerium für Umwelt und Verbraucherschutz, Deutsches Zentrum für Lungenforschung, Lungenliga Schweiz, Gemeinsame Bundesausschuss, Lietuvos Sveikatos Mokslų Universitetas, International Science and Technology Cooperation Program of Shanxi Province, National Institutes of Health, University of Texas Health Science Center at San Antonio, Horizon 2020 Framework Programme, Canadian Institutes of Health Research, Center on Aging, University of Utah, Economic and Social Research Council, National Health and Medical Research Council, Science and Engineering Research Board, European Regional Development Fund, National Key Research and Development Program of China, Key Laboratory of Agricultural Information Service Technology, Conselleria de Innovación, Universidades, Ciencia y Sociedad Digital, Generalitat Valenciana, Zürcher Hochschule für Angewandte Wissenschaften, National Institute on Aging, National Heart, Lung, and Blood Institute, National Institute of Mental Health, National Institute on Drug Abuse, NIH Office of the Director, National Cancer Institute, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institute of Biomedical Imaging and Bioengineering, National Center for Advancing Translational Sciences, National Institute on Minority Health and Health Disparities, Moonshot Research and Development Program, HORIZON EUROPE European Research Council
OpenAlex ID: W7124776018