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  A new dominant peroxiredoxin allele identified by whole-genome re-sequencing of random mutagenized yeast causes oxidant-resistance and premature aging.

Timmermann, B., Jarolim, S., Russmayer, H., Kerick, M., Michel, S., Krüger, A., et al. (2010). A new dominant peroxiredoxin allele identified by whole-genome re-sequencing of random mutagenized yeast causes oxidant-resistance and premature aging. Aging (Albany NY), 2(8), 475-486. Retrieved from http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=20729566 %> internal-pdf://Timmermann-2010-A new dominant perox-4086131712/Timmermann-2010-A new dominant perox.pdf.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0010-7A8A-A Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0010-7A8B-8
Genre: Journal Article
Alternative Title : Aging (Albany NY)

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 Creators:
Timmermann, B.1, Author              
Jarolim, S., Author
Russmayer, H.2, Author
Kerick, M.3, Author              
Michel, S.4, Author              
Krüger, A.4, Author              
Bluemlein, K.4, Author              
Laun, P., Author
Grillari, J., Author
Lehrach, H.4, Author              
Breitenbach, M., Author
Ralser, M.4, Author              
Affiliations:
1Sequencing, Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433559              
2Max Planck Society, ou_persistent13              
3Cancer Genomics (Michal-Ruth Schweiger), Dept. of Vertebrate Genomics (Head: Hans Lehrach), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479649              
4Dept. of Vertebrate Genomics (Head: Hans Lehrach), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433550              

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Free keywords: Aging, whole genome resequencing, redox homeostasis, peroxiredoxin
 Abstract: The combination of functional genomics with next generation sequencing facilitates new experimental strategies for addressing complex biological phenomena. Here, we report the identification of a gain-of-function allele of peroxiredoxin (thioredoxin peroxidase, Tsa1p) via whole-genome re-sequencing of a dominantSaccharomyces cerevisiae mutant obtained by chemical mutagenesis. Yeast strain K6001, a screening system for lifespan phenotypes, was treated with ethyl methanesulfonate (EMS). We isolated an oxidative stress-resistant mutant (B7) which transmitted this phenotype in a background-independent, monogenic and dominant way. By massive parallel pyrosequencing, we generated an 38.8 fold whole-genome coverage of the strains, which differed in 12,482 positions from the reference (S288c) genome. Via a subtraction strategy, we could narrow this number to 13 total and 4 missense nucleotide variations that were specific for the mutant. Via expression in wild type backgrounds, we show that one of these mutations, exchanging a residue in the peroxiredoxin Tsa1p, was responsible for the mutant phenotype causing background-independent dominant oxidative stress-resistance. These effects were not provoked by altered Tsa1p levels, nor could they be simulated by deletion, haploinsufficiency or over-expression of the wild-type allele. Furthermore, via both a mother-enrichment technique and a micromanipulation assay, we found a robust premature aging phenotype of this oxidant-resistant strain. Thus, TSA1-B7 encodes for a novel dominant form of peroxiredoxin, and establishes a new connection between oxidative stress and aging. In addition, this study shows that the re-sequencing of entire genomes is becoming a promising alternative for the identification of functional alleles in approaches of classic molecular genetics.

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Language(s): eng - English
 Dates: 2010-08-13
 Publication Status: Published in print
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Title: Aging (Albany NY)
  Alternative Title : Aging (Albany NY)
Source Genre: Journal
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Pages: - Volume / Issue: 2 (8) Sequence Number: - Start / End Page: 475 - 486 Identifier: ISSN: 1945-4589