Thiol peroxidase deficiency leads to increased mutational load and decreased fitness in saccharomyces cerevisiae

Alaattin Kaya, Alexei V. Lobanov, Maxim V. Gerashchenko, Amnon Koren, Dmitri E. Fomenko, Ahmet Koc, Vadim N. Gladyshev

Research output: Contribution to journalArticle

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Abstract

Thiol peroxidases are critical enzymes in the redox control of cellular processes that function by reducing low levels of hydroperoxides and regulating redox signaling. These proteins were also shown to regulate genome stability, but how their dysfunction affects the actual mutations in the genome is not known. Saccharomyces cerevisiae has eight thiol peroxidases of glutathione peroxidase and peroxiredoxin families, and the mutant lacking all these genes (Δ8) is viable. In this study, we employed two independent Δ8 isolates to analyze the genome-wide mutation spectrum that results from deficiency in these enzymes. Deletion of these genes was accompanied by a dramatic increase in point mutations, many of which clustered in close proximity and scattered throughout the genome, suggesting strong mutational bias. We further subjected multiple lines of wild-type and Δ8 cells to long-term mutation accumulation, followed by genome sequencing and phenotypic characterization. Δ8 lines showed a significant increase in nonrecurrent point mutations and indels. The original Δ8 cells exhibited reduced growth rate and decreased life span, which were further reduced in all Δ8 mutation accumulation lines. Although the mutation spectrum of the two independent isolates was different, similar patterns of gene expression were observed, suggesting the direct contribution of thiol peroxidases to the observed phenotypes. Expression of a single thiol peroxidase could partially restore the growth phenotype of Δ8 cells. This study shows how deficiency in nonessential, yet critical and conserved oxidoreductase function, leads to increased mutational load and decreased fitness.

Original languageEnglish (US)
Pages (from-to)905-917
Number of pages13
JournalGenetics
Volume198
Issue number3
DOIs
StatePublished - Nov 1 2014

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Sulfhydryl Compounds
Peroxidases
Peroxidase
Saccharomyces cerevisiae
Genome
Point Mutation
Mutation
Oxidation-Reduction
Peroxiredoxins
Phenotype
Genomic Instability
Gene Deletion
Enzymes
Growth
Glutathione Peroxidase
Hydrogen Peroxide
Oxidoreductases
Gene Expression
Genes
Proteins

ASJC Scopus subject areas

  • Genetics

Cite this

Thiol peroxidase deficiency leads to increased mutational load and decreased fitness in saccharomyces cerevisiae. / Kaya, Alaattin; Lobanov, Alexei V.; Gerashchenko, Maxim V.; Koren, Amnon; Fomenko, Dmitri E.; Koc, Ahmet; Gladyshev, Vadim N.

In: Genetics, Vol. 198, No. 3, 01.11.2014, p. 905-917.

Research output: Contribution to journalArticle

Kaya, Alaattin ; Lobanov, Alexei V. ; Gerashchenko, Maxim V. ; Koren, Amnon ; Fomenko, Dmitri E. ; Koc, Ahmet ; Gladyshev, Vadim N. / Thiol peroxidase deficiency leads to increased mutational load and decreased fitness in saccharomyces cerevisiae. In: Genetics. 2014 ; Vol. 198, No. 3. pp. 905-917.
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