To understand the mechanisms underlying aging and cancer due to
mitochondrial dysfunction we tested whether mitconhondrial dysfunction
impacts on the genetic stability of the nuclear genome. Using
Saccharomyces cerevisiae as a model organism, we analyzed the
consequences of disrupting mitochondrial function on genetic stability
of the nuclear genome. In wild type yeast exposed to mitochondrial
respiratory chain inhibitors or mutant yeast lacking the entire
mitochondrial genome (rho0) or yeast with a mitochondrial mutation
(rho-), we tested the instability of the nuclear genome by measuring
the frequency of canavanine resistant colonies. The CAN1 gene of S.
cerevisiae encodes a transmembrane amino acid transporter that renders
the cell sensitive to lethal arginine analogue, canavanine. Any
inactivating mutation in this gene results in a canavanine resistant
phenotype (CANR). We calculated the frequency of canavanine resistant
colonies as a measure of spontaneous nuclear mutational events in rho0
and rho- strains. We found that, compared to the wild type cells,
nuclear mutational events were significantly higher in both rho0 and
rho- strains. Likewise, inhibition of electron transport by antimycin
and other agents in wild type cells resulted in increase frequency of
mutation in nuclear genome. Our studies have also revealed that REV1,
REV3 or REV7 gene products, implicated in error-prone translesion DNA
synthesis, mediate the genetic instability of the nuclear genome
arising as a result of mitochondrial dysfunction. Our results described
here in yeast model provide a direct link between mitochondrial
dysfunction and genetic instability, which has important implications
in human cancer and aging.
Key words:
aging, cancer, mitochondria, mutator phenotype, mutation
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