title: Spontaneous DNA damage in Saccharomyces cerevisiae elicits phenotypic properties similar to cancer cells.
abstract: To determine the spectrum of effects elicited by specific levels of spontaneous DNA damage, a series of isogenic Saccharomyces cerevisiae strains defective in base excision repair (BER) and nucleotide excision repair (NER) were analyzed. In log phase of growth, when compared with wild type (WT) or NER-defective cells, BER-defective cells and BER/NER-defective cells possess elevated levels of unrepaired, spontaneous oxidative DNA damage. This system allowed establishment of a range of approximately 400 to 1400 Ntg1p-recognized DNA lesions per genome necessary to provoke profound biological changes similar in many respects to the phenotypic properties of cancer cells. The BER/NER-defective cells are genetically unstable, exhibiting mutator and hyper-recombinogenic phenotypes. They also exhibit aberrations in morphology, DNA content, and growth characteristics compared with WT, BER-defective, and NER-defective cells. The BER/NER-defective cells also possess increased levels of intracellular reactive oxygen species, activate the yeast checkpoint response pathway via Rad53p phosphorylation in stationary phase, and show profound changes in transcription patterns, a subset of which can be ascribed to responses resulting from unrepaired DNA damage. By establishing a relationship between specific levels of spontaneous DNA damage and the ensuing deleterious biological consequences, these yeast DNA excision repair-defective strains are an informative model for gauging the progressive biological consequences of spontaneous DNA damage accumulation and may have relevancy for delineating underlying mechanisms in tumorigenesis.
authors.affiliation: Department of Biochemistry, Graduate Program in Genetics and Molecular Biology, School of Medicine, Emory University, Atlanta, Georgia, 30322, USA.
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Evert
authors.forename: Tiffany B
authors.initials: TB
authors.lastname: Salmon
authors.forename: Binwei
authors.initials: B
authors.lastname: Song
authors.forename: Liu
authors.initials: L
authors.lastname: Jingjing
authors.forename: Wolfram
authors.initials: W
authors.lastname: Siede
authors.forename: Paul W
authors.initials: PW
authors.lastname: Doetsch
mesh_terms: D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division; D002470:Cell Survival; D064447:Checkpoint Kinase 2; D002869:Chromosome Aberrations; D004247:DNA / Q000737:chemistry; D004249:DNA Damage; D004260:DNA Repair; D005434:Flow Cytometry; D016681:Genome, Fungal; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000378:metabolism*; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D010100:Oxygen / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017382:Reactive Oxygen Species; D011995:Recombination, Genetic; D012441:Saccharomyces cerevisiae / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014158:Transcription, Genetic
chemical_list: D018797:Cell Cycle Proteins; D017382:Reactive Oxygen Species; D029701:Saccharomyces cerevisiae Proteins; D004247:DNA; D064447:Checkpoint Kinase 2; D017346:Protein Serine-Threonine Kinases; C067022:RAD53 protein, S cerevisiae; D010100:Oxygen