Targeting of a gene to the nuclear pore complexes (NPCs), known as gene gating, can affect its transcriptional state. However, the mechanism underlying gene gating is poorly understood. Here, we have identified SAGA-associated Sgf73 (ref. 10), the yeast orthologue of human Ataxin-7 (ref. 11), as a regulator of histone H2B ubiquitin levels, a modification linked to both transcription initiation and elongation. Sgf73 is a key component of a minimal histone-deubiquitinating complex. Activation of the H2B deubiquitinating protease, Ubp8, is cooperative and requires complex formation with the amino-terminal zinc-finger-containing domain of Sgf73 and Sgf11-Sus1. Through a separate domain, Sgf73 mediates recruitment of the TREX-2 mRNA export factors Sac3 and Thp1 to SAGA and their stable interaction with Sus1-Cdc31. This latter step is crucial to target TREX-2 to the NPC. Loss of Sgf73 from SAGA abrogates gene gating of GAL1 and causes a GAL1 mRNA export defect. Thus, Sgf73 provides a molecular scaffold to integrate the regulation of H2B ubiquitin levels, tethering of a gene to the NPC and export of mRNA.
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"A relay between nucleoporins and transcription could operate through an intermediate layer of adaptor proteins. Known candidates are the chromatin modifier SAGA (Kö hler et al., 2008; Rodríguez-Navarro et al., 2004), the THO complex (Rougemaille et al., 2008), and the TREX-2 complex (Cabal et al., 2006). Specialized promoter elements (Ahmed et al., 2010) and the post-translational modification of transcription factors (Texari et al., 2013) further contribute to transient gene-NPC contacts. "
"Previous work has indicated that Mex67:Mtr2 binds primarily to the N-terminal region of Sac3 (Fischer et al., 2002). In yeast, TREX-2 also facilitates the localization of many actively transcribing genes, such as GAL1, to NPCs, which in turn facilitates the removal of repression mediated by de-ubiquitinylation by Ulp1 (Texari et al., 2013) and, through interactions between TREX-2 and the SAGA complex, can couple transcription, processing, and polyadenylation with the export of mature mRNAs to the cytoplasm (Rodriguez-Navarro et al., 2004; Kö hler et al., 2008). Although crystal structures have been obtained for parts of the Saccharomyces TREX-2 complex, such as Sac3 CID bound to Sus1 and Cdc31 (Jani et al., 2009, 2014 "
"Sus1 has other functions in addition to its activity in SAGA, which may make its role in yeast RLS unpredictable. Strains lacking both SGF73 and UBP8 have lifespans identical to the SGF73 single deletion, consistent with the prediction that both deletions enhance lifespan by a similar mechanism and cause increased levels of ubiquitinated H2B (Figure S1B) (Kö hler et al., 2008). "
[Show abstract][Hide abstract] 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.