Oncogene homologue Sch9 promotes age-dependent mutations by a superoxide and Rev1/Polzeta-dependent mechanism.
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.
Madia
Federica
F
Andrus Gerontology Center and Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA.
Wei
Min
M
Yuan
Valerie
V
Hu
Jia
J
Gattazzo
Cristina
C
Pham
Phuong
P
Goodman
Myron F
MF
Longo
Valter D
VD
D000375:Aging / Q000502:physiology; D026923:Amino Acid Transport Systems, Basic / Q000235:genetics / Q000378:metabolism; D000818:Animals; D004249:DNA Damage; D004259:DNA-Directed DNA Polymerase / Q000235:genetics / Q000378:metabolism; D017353:Gene Deletion; D042822:Genomic Instability; D056466:Histone Demethylases; D006801:Humans; D008017:Life Expectancy; D009713:Nucleotidyltransferases / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D017354:Point Mutation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000502:physiology*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism*; D000099270:Y-Family DNA Polymerases
D026923:Amino Acid Transport Systems, Basic; D004259:DNA-Directed DNA Polymerase; D056466:Histone Demethylases; D009713:Nucleotidyltransferases; D017346:Protein Serine-Threonine Kinases; D000090063:Proto-Oncogene Mas; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; D013481:Superoxides; C502212:CAN1 protein, S cerevisiae; C000715470:MAS1 protein, human; C400297:GIS1 protein, S cerevisiae; C530964:SCH9 protein, S cerevisiae; C425929:DNA polymerase zeta; C100951:REV1 protein, S cerevisiae; D000099270:Y-Family DNA Polymerases
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