Polymorphisms in DNA polymerase γ affect the mtDNA stability and the NRTI-induced mitochondrial toxicity in Saccharomyces cerevisiae

Mitochondrion. 2015 Jan:20:52-63. doi: 10.1016/j.mito.2014.11.003. Epub 2014 Nov 18.

Abstract

Several pathological mutations have been identified in human POLG gene, encoding for the catalytic subunit of Pol γ, the solely mitochondrial replicase in animals and fungi. However, little is known regarding non-pathological polymorphisms found in this gene. Here we studied, in the yeast model Saccharomyces cerevisiae, eight human polymorphisms. We found that most of them are not neutral but enhanced both mtDNA extended mutability and the accumulation of mtDNA point mutations, either alone or in combination with a pathological mutation. In addition, we found that the presence of some SNPs increased the stavudine and/or zalcitabine-induced mtDNA mutability and instability.

Keywords: MIP1; NRTI; POLG polymorphisms; Pharmacogenetics; Yeast model; mtDNA point and extended mutability.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA Polymerase gamma
  • DNA, Mitochondrial / genetics
  • DNA, Mitochondrial / metabolism*
  • DNA-Directed DNA Polymerase / genetics*
  • DNA-Directed DNA Polymerase / metabolism*
  • Genomic Instability*
  • Humans
  • Mitochondria / drug effects
  • Point Mutation
  • Polymorphism, Single Nucleotide*
  • Reverse Transcriptase Inhibitors / pharmacology
  • Saccharomyces cerevisiae / enzymology*
  • Saccharomyces cerevisiae / genetics
  • Stavudine / pharmacology*
  • Zalcitabine / pharmacology

Substances

  • DNA, Mitochondrial
  • Reverse Transcriptase Inhibitors
  • Zalcitabine
  • Stavudine
  • DNA Polymerase gamma
  • DNA-Directed DNA Polymerase
  • POLG protein, human