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Genetics. 2014 Nov;198(3):905-17. doi: 10.1534/genetics.114.169243. Epub 2014 Aug 29.

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

Author information

1
Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115.
2
Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115.
3
Department of Biochemistry and Redox Biology Center, University of Nebraska, Lincoln, Nebraska 68588.
4
Department of Molecular Biology and Genetics, Izmir Institute of Technology, 35430 Urla, Izmir, Turkey.
5
Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115 vgladyshev@rics.bwh.harvard.edu.

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 (∆8) is viable. In this study, we employed two independent ∆8 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 ∆8 cells to long-term mutation accumulation, followed by genome sequencing and phenotypic characterization. ∆8 lines showed a significant increase in nonrecurrent point mutations and indels. The original ∆8 cells exhibited reduced growth rate and decreased life span, which were further reduced in all ∆8 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 ∆8 cells. This study shows how deficiency in nonessential, yet critical and conserved oxidoreductase function, leads to increased mutational load and decreased fitness.

KEYWORDS:

Saccharomyces cerevisiae; genome stability; mutation; thiol peroxidase

PMID:
25173844
PMCID:
PMC4224179
DOI:
10.1534/genetics.114.169243
[Indexed for MEDLINE]
Free PMC Article

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