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Studying Age-dependent Genomic Instability using the S. cerevisiae Chronological Lifespan Model
08:46

Studying Age-dependent Genomic Instability using the S. cerevisiae Chronological Lifespan Model

Published on: September 29, 2011

Oncogene homologue Sch9 promotes age-dependent mutations by a superoxide and Rev1/Polzeta-dependent mechanism

Federica Madia1, Min Wei, Valerie Yuan

  • 1Andrus Gerontology Center and Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA.

The Journal of Cell Biology
|August 19, 2009
PubMed

Insights

The yeast protein Sch9 promotes DNA damage and mutations during aging in non-dividing cells. Reducing this damage may prevent genomic instability and cell death.

Area of Science:

  • Cellular and Molecular Biology
  • Genetics and Genomics
  • Aging Research

Background:

  • Oncogenes drive cancer by promoting cell growth and survival.
  • Sch9 in yeast is homologous to mammalian Akt and S6 kinase, involved in cell growth pathways.
  • Genomic instability and DNA damage accumulate during cellular aging, particularly in non-dividing cells.

Purpose of the Study:

  • To investigate the role of Sch9 in DNA damage and genomic instability during aging in non-dividing yeast cells.
  • To elucidate the mechanisms by which Sch9 influences age-dependent DNA alterations.
  • To explore potential strategies for mitigating age-related DNA damage.

Main Methods:

  • Analysis of DNA damage markers (base substitutions, insertions/deletions, GCRs) in wild-type and sch9Delta mutant yeast strains.
  • Measurement of oxidative stress markers, including DNA oxidation and superoxide dismutase (SOD) expression.
  • Assessment of REV1 expression and translesion synthesis (TLS) activity.
  • Genetic manipulation of SOD genes (SOD1, SOD2) and DNA repair pathways (Polzeta, REV1) in SCH9 overexpressing strains.

Main Results:

  • sch9Delta mutants exhibited attenuated age-dependent increases in base substitutions, DNA insertions/deletions, and GCRs.
  • This attenuation correlated with increased mitochondrial superoxide dismutase (MnSOD) expression, decreased DNA oxidation, and reduced REV1 expression/TLS.
  • While REV1 deficiency or altered SOD levels reduced point mutations in SCH9 overexpressors, REV1 deficiency significantly increased GCRs.

Conclusions:

  • The proto-oncogene homologue Sch9 promotes superoxide-dependent DNA damage accumulation in aging, non-dividing cells.
  • This damage triggers error-prone DNA repair mechanisms, favoring point mutations over GCRs to prevent cell death during replication.
  • Sch9's function highlights a link between oncogenic pathways, oxidative stress, and age-related genomic instability.

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