title: The SAGA histone deubiquitinase module controls yeast replicative lifespan via Sir2 interaction.
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.
authors.affiliation: Buck Institute for Research on Aging, Novato, CA 94945, USA; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: McCormick
authors.affiliation: 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.
authors.forename: Amanda G
authors.initials: AG
authors.lastname: Mason
authors.affiliation: Department of Medical Genetics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Stephan J
authors.initials: SJ
authors.lastname: Guyenet
authors.affiliation: 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.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Dang
authors.affiliation: 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.
authors.forename: Renee M
authors.initials: RM
authors.lastname: Garza
authors.affiliation: Buck Institute for Research on Aging, Novato, CA 94945, USA.
authors.forename: Marc K
authors.initials: MK
authors.lastname: Ting
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Rick M
authors.initials: RM
authors.lastname: Moller
authors.affiliation: Department of Cell and Developmental Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Shelley L
authors.initials: SL
authors.lastname: Berger
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Matt
authors.initials: M
authors.lastname: Kaeberlein
authors.affiliation: University of California, San Diego, Moores Cancer Center, La Jolla, CA 92093, USA; Department of Pathology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Lorraine
authors.initials: L
authors.lastname: Pillus
authors.affiliation: 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.
authors.forename: Albert R
authors.initials: AR
authors.lastname: La Spada
authors.affiliation: 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.
authors.forename: Brian K
authors.initials: BK
authors.lastname: Kennedy
mesh_terms: D049109:Cell Proliferation; D004261:DNA Replication; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D056565:Sirtuin 2 / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
chemical_list: D010450:Endopeptidases; D051548:Histone Acetyltransferases; D029701:Saccharomyces cerevisiae Proteins; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae; D056565:Sirtuin 2; D015534:Trans-Activators; C507785:SAGA complex, S cerevisiae; C501392:GCN5 protein, S cerevisiae; D000099224:p300-CBP-Associated Factor; C515833:Sgf73 protein, S cerevisiae; C503322:UBP8 protein, S cerevisiae; C087778:SIR2 protein, S cerevisiae