Abstract
Oncogenes contribute to tumorigenesis by promoting growth and inhibiting apoptosis. Here we examine the function of Sch9, the Saccharomyces cerevisiae homologue of the mammalian Akt and S6 kinase, in DNA damage and genomic instability during aging in nondividing cells. Attenuation of age-dependent increases in base substitutions, small DNA insertions/deletions, and gross chromosomal rearrangements (GCRs) in sch9Delta mutants is associated with increased mitochondrial superoxide dismutase (MnSOD) expression, decreased DNA oxidation, reduced REV1 expression and translesion synthesis, and elevated resistance to oxidative stress-induced mutagenesis. Deletion of REV1, the lack of components of the error-prone Polzeta, or the overexpression of SOD1 or SOD2 is sufficient to reduce age-dependent point mutations in SCH9 overexpressors, but REV1 deficiency causes a major increase in GCRs. These results suggest that the proto-oncogene homologue Sch9 promotes the accumulation of superoxide-dependent DNA damage in nondividing cells, which induces error-prone DNA repair that generates point mutations to avoid GCRs and cell death during the first round of replication.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Aging / physiology
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Amino Acid Transport Systems, Basic / genetics
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Amino Acid Transport Systems, Basic / metabolism
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Animals
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DNA Damage
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DNA-Directed DNA Polymerase / genetics
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DNA-Directed DNA Polymerase / metabolism
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Gene Deletion
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Genomic Instability
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Histone Demethylases
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Humans
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Life Expectancy
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Nucleotidyltransferases / genetics
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Nucleotidyltransferases / metabolism*
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Oligonucleotide Array Sequence Analysis
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Oxidation-Reduction
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Oxidative Stress
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Point Mutation*
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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Proto-Oncogene Mas
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Repressor Proteins / genetics
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Repressor Proteins / metabolism
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Saccharomyces cerevisiae / cytology
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Saccharomyces cerevisiae / physiology*
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Saccharomyces cerevisiae Proteins / genetics
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Saccharomyces cerevisiae Proteins / metabolism*
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Superoxides / metabolism*
Substances
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Amino Acid Transport Systems, Basic
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CAN1 protein, S cerevisiae
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MAS1 protein, human
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Proto-Oncogene Mas
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Repressor Proteins
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Saccharomyces cerevisiae Proteins
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Superoxides
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GIS1 protein, S cerevisiae
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Histone Demethylases
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Protein Serine-Threonine Kinases
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SCH9 protein, S cerevisiae
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DNA polymerase zeta
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Nucleotidyltransferases
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REV1 protein, S cerevisiae
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DNA-Directed DNA Polymerase