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

Abstract

SUMMARY We have analyzed the yeast replicative lifespan of a large number of 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 pro-longevity events, including reduced rDNA recombination and altered silencing of telomere-proximal genes. As 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.

Sharing the cell's bounty – organelle inheritance in yeast

“…Consistent with this hypothesis are observations that the expression of high-copy number plasmids reduces replicative lifespan (Falcón and Aris, 2003), whereas lowering the frequency of recombination at the rDNA locus leads to lifespan extension (McCormick et al, 2014). rDNA circles are segregated unevenly between mother and daughter cells, with a retention frequency of .98% by the mother cell nucleus (Sinclair and Guarente, 1997).…”

The Epigenetic Pathways to Ribosomal DNA Silencing

“…Yeast Ubp10 was previously reported to be required for proper Sir2 localization at the telomeric and rDNA regions by maintaining low levels of H2BK123 ubiquitylation as well as low levels of H3K4 and H3K79 methylation within telomeric and rDNA loci (103,104). In contrast to the role of Ubp10, cells that are deficient in the SAGA histone deubiquitylase module, including Ubp8, are exceptionally long-lived (173).…”

A budding yeast's perspective on aging: The shape I'm in

“…Similar lifespan curves have been seen in rad6D and rpt1sD mutants. 30,140 Nonetheless, these cells appear to be aging slower than wild type cells. Conversely, in the complete absence of aging, lifespan curves would display the consistency of a decaying exponential (constant line in Figure 3b).…”

“…28,29 Sir2 has also been shown to interact with the histone deubiquitinase module component Sgf73 (the yeast ortholog of human ataxin-7). 30 Dependent on the presence of Sir2, deletion of SGF73 significantly increases RLS, possibly by increasing silencing and repression of rDNA recombination. 30 Functionally, Sir2 is an NAD þ -dependent deacetylase, and thus its activity is linked to intracellular NAD þ concentrations and fluctuations.…”

“…30 Dependent on the presence of Sir2, deletion of SGF73 significantly increases RLS, possibly by increasing silencing and repression of rDNA recombination. 30 Functionally, Sir2 is an NAD þ -dependent deacetylase, and thus its activity is linked to intracellular NAD þ concentrations and fluctuations. 31,32 The deacetylation reaction produces nicotinamide (NAM), a potent inhibitor of Sir2 activity.…”