A mutation-promotive role of nucleotide excision repair in cell cycle-arrested cell populations following UV irradiation.
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.
Heidenreich
Erich
E
Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Borschkegasse 8a, Vienna, Austria. erich.heidenreich@meduniwien.ac.at
Eisler
Herfried
H
Lengheimer
Theresia
T
Dorninger
Petra
P
Steinboeck
Ferdinand
F
D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle; D002470:Cell Survival / Q000528:radiation effects; D004260:DNA Repair / Q000528:radiation effects*; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism; D004271:DNA, Fungal / Q000378:metabolism*; D009154:Mutation / Q000528:radiation effects*; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism* / Q000528:radiation effects*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D014466:Ultraviolet Rays
D004271:DNA, Fungal; C072975:RAD14 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D000251:Adenosine Triphosphatases; C075467:RAD16 protein, S cerevisiae; C465758:RAD26 protein, S cerevisiae; D045643:DNA Repair Enzymes