title: Polymorphisms in DNA polymerase γ affect the mtDNA stability and the NRTI-induced mitochondrial toxicity in Saccharomyces cerevisiae.
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.
authors.affiliation: Department of Life Sciences, University of Parma, Parma, Italy. Electronic address: enrico.baruffini@unipr.it.
authors.forename: Enrico
authors.initials: E
authors.lastname: Baruffini
authors.affiliation: Department of Life Sciences, University of Parma, Parma, Italy.
authors.forename: Jessica
authors.initials: J
authors.lastname: Ferrari
authors.affiliation: Department of Life Sciences, University of Parma, Parma, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Dallabona
authors.affiliation: Department of Life Sciences, University of Parma, Parma, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Donnini
authors.affiliation: Department of Life Sciences, University of Parma, Parma, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Lodi
mesh_terms: D000074002:DNA Polymerase gamma; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism*; D004259:DNA-Directed DNA Polymerase / Q000235:genetics* / Q000378:metabolism*; D042822:Genomic Instability; D006801:Humans; D008928:Mitochondria / Q000187:drug effects; D017354:Point Mutation; D020641:Polymorphism, Single Nucleotide; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology; D012441:Saccharomyces cerevisiae / Q000201:enzymology* / Q000235:genetics; D018119:Stavudine / Q000494:pharmacology*; D016047:Zalcitabine / Q000494:pharmacology
chemical_list: D004272:DNA, Mitochondrial; D018894:Reverse Transcriptase Inhibitors; D016047:Zalcitabine; D018119:Stavudine; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C413027:POLG protein, human
keywords: MIP1; NRTI; POLG polymorphisms; Pharmacogenetics; Yeast model; mtDNA point and extended mutability