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Cell Rep. 2014 Jul 24;8(2):477-86. doi: 10.1016/j.celrep.2014.06.037. Epub 2014 Jul 18.

The SAGA histone deubiquitinase module controls yeast replicative lifespan via Sir2 interaction.

Author information

1
Buck Institute for Research on Aging, Novato, CA 94945, USA; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
2
Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA; Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
3
Department of Medical Genetics, University of Washington, Seattle, WA 98195, USA.
4
Department of Cell and Developmental Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Huffington Center on Aging, Baylor College of Medicine, Houston, TX 76798, USA.
5
Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA; University of California, San Diego, Moores Cancer Center, La Jolla, CA 92093, USA.
6
Buck Institute for Research on Aging, Novato, CA 94945, USA.
7
Department of Pathology, University of Washington, Seattle, WA 98195, USA.
8
Department of Cell and Developmental Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
9
University of California, San Diego, Moores Cancer Center, La Jolla, CA 92093, USA; Department of Pathology, University of Washington, Seattle, WA 98195, USA.
10
Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA; Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA; Department of Medical Genetics, University of Washington, Seattle, WA 98195, USA; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Department of Neuroscience, University of California, San Diego, La Jolla, CA 92093, USA; Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: alaspada@ucsd.edu.
11
Buck Institute for Research on Aging, Novato, CA 94945, USA; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA. Electronic address: bkennedy@buckinstitute.org.

Abstract

We have analyzed the yeast replicative lifespan of a large number of open reading frame (ORF) deletions. Here, we report that strains lacking genes SGF73, SGF11, and UBP8 encoding SAGA/SLIK complex histone deubiquitinase module (DUBm) components are exceptionally long lived. Strains lacking other SAGA/SALSA components, including the acetyltransferase encoded by GCN5, are not long lived; however, these genes are required for the lifespan extension observed in DUBm deletions. Moreover, the SIR2-encoded histone deacetylase is required, and we document both a genetic and physical interaction between DUBm and Sir2. A series of studies assessing Sir2-dependent functions lead us to propose that DUBm strains are exceptionally long lived because they promote multiple prolongevity events, including reduced rDNA recombination and altered silencing of telomere-proximal genes. Given that ataxin-7, the human Sgf73 ortholog, causes the neurodegenerative disease spinocerebellar ataxia type 7, our findings indicate that the genetic and epigenetic interactions between DUBm and SIR2 will be relevant to neurodegeneration and aging.

PMID:
25043177
PMCID:
PMC4284099
DOI:
10.1016/j.celrep.2014.06.037
[Indexed for MEDLINE]
Free PMC Article

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