A mutation-promotive role of nucleotide excision repair in cell cycle-arrested cell populations following UV irradiation |
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| Authors: | Erich Heidenreich Herfried Eisler Theresia Lengheimer Petra Dorninger Ferdinand Steinboeck |
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| Institution: | 1. Research School of Chemistry, Australian National University, Australian Capital Territory 0200, Australia;2. New England Regional Primate Research Center, Harvard Medical School, Southboro, MA 01772, USA;3. University of Massachusetts Medical School, 55 Lake Avenue, Worcester, MA 01655, USA;4. Department of Physiology & Pennsylvania Muscle Institute, University of Pennsylvania, School of Medicine, Philadelphia, PA 19104, USA;1. Instituto Multidisciplinario de Biología Vegetal (FCEFyN, CONICET-Universidad Nacional de Córdoba), Av. Vélez Sarsfield 1611, CC495, CP5000, Córdoba, Argentina;2. Facultad de Ciencias Forestales, Universidad Autónoma de Nuevo León, A.P. 41, Carretera Nacional No. 85, Km 145, C.P. 67700, Linares, N.L., Mexico;3. Instituto Potosino de Investigación Científica y Tecnológica, A.C., Camino a la Presa San José No. 2055. Col. Lomas 4a. Sección, C.P. 78216, San Luis Potosí, S.L.P., Mexico;1. Unit of Molecular Genetics of Aging and Laboratory of Epigenetics, Department of Ecology and Biology, University of Tuscia, 01100 Viterbo, Italy |
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| Abstract: | Growing attention is paid to the concept that mutations arising in stationary, non-proliferating cell populations considerably contribute to evolution, aging, and pathogenesis. If such mutations are beneficial to the affected cell, in the sense of allowing a restart of proliferation, they are called adaptive mutations. In order to identify cellular processes responsible for adaptive mutagenesis in eukaryotes, we study frameshift mutations occurring during auxotrophy-caused cell cycle arrest in the model organism Saccharomyces cerevisiae. Previous work has shown that an exposure of cells to UV irradiation during prolonged cell cycle arrest resulted in an increased incidence of mutations. In the present work, we determined the influence of defects in the nucleotide excision repair (NER) pathway on the incidence of UV-induced adaptive mutations in stationary cells. The mutation frequency was decreased in Rad16-deficient cells and further decreased in Rad16/Rad26 double-deficient cells. A knockout of the RAD14 gene, the ortholog of the human XPA gene, even resulted in a nearly complete abolishment of UV-induced mutagenesis in cell cycle-arrested cells. Thus, the NER pathway, responsible for a normally accurate repair of UV-induced DNA damage, paradoxically is required for the generation and/or fixation of UV-induced frameshift mutations specifically in non-replicating cells. |
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