The SAGA Histone Deubiquitinase Module Controls Yeast Replicative Lifespan via Sir2 Interaction

• Published in: Cell reports (Cambridge) 2014-07, Vol.8 (2), p.477-486
• Main Authors: McCormick, Mark A., Mason, Amanda G., Guyenet, Stephan J., Dang, Weiwei, Garza, Renee M., Ting, Marc K., Moller, Rick M., Berger, Shelley L., Kaeberlein, Matt, Pillus, Lorraine, La Spada, Albert R., Kennedy, Brian K.
• Format: Article
• Language: English
• Subjects: Cell Proliferation; DNA Replication; Endopeptidases - genetics; Endopeptidases - metabolism; Histone Acetyltransferases - genetics; Histone Acetyltransferases - metabolism; Protein Binding; Saccharomyces cerevisiae - genetics; Saccharomyces cerevisiae - metabolism; Saccharomyces cerevisiae - physiology; Saccharomyces cerevisiae Proteins - genetics; Saccharomyces cerevisiae Proteins - metabolism; Silent Information Regulator Proteins, Saccharomyces cerevisiae - genetics; Silent Information Regulator Proteins, Saccharomyces cerevisiae - metabolism; Sirtuin 2 - genetics; Sirtuin 2 - metabolism; Trans-Activators - genetics; Trans-Activators - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2014.06.037

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. [Display omitted] •Yeast lacking SGF73 are extremely long lived due to Ubp8 loss and increased Sir2 action•Sir2 shows genetic and physical interaction with Sgf73 of the SAGA complex•Sgf73 ortholog ataxin-7 causes SCA7, suggesting relevance to human neurodegeneration McCormick et al. now examine the yeast replicative lifespan of a large number of ORF deletions and find that strains lacking genes SGF73, SGF11, and UBP8 encoding SAGA/SLIK complex histone deubiquitinase module (DUBm) components are exceptionally long lived. The SIR2 histone deacetylase is required for this effect, and the authors document both a genetic and physical interaction between DUBm and Sir2. Given that ataxin-7, the human Sgf73 ortholog, causes the neurodegenerative disease spinocerebellar ataxia type 7, these findings may prove to be relevant to neurodegeneration and aging.