Crystal Structures of the S. cerevisiae Spt6 Core and C-Terminal Tandem SH2 Domain

Close, Devin; Johnson, Sean; Sdano, Matthew A.; McDonald, S.M.; Robinson, Howard; Formosa, Tim; Hill, Christopher P.

doi:10.1016/j.jmb.2011.03.002

Cited by 55 publications

(86 citation statements)

References 65 publications

(101 reference statements)

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“…Spt6 is a large protein (1451 amino acids in S. cerevisiae) with multiple domains that suggest interactions with DNA, RNA, and several proteins in addition to Spn1 (Doherty et al 1996;Johnson et al 2008;Dengl et al 2009;Close et al 2011). Among its domains are tandem SH2 domains at its carboxy-terminal end, the only SH2 domains in S. cerevisiae (Maclennan and Shaw 1993;Dengl et al 2009;Diebold et al 2010b;Sun et al 2010;Close et al 2011;Liu et al 2011).…”

Section: Spt6 and Fact: Factors Controlling Transcriptional Integritymentioning

confidence: 99%

“…Among its domains are tandem SH2 domains at its carboxy-terminal end, the only SH2 domains in S. cerevisiae (Maclennan and Shaw 1993;Dengl et al 2009;Diebold et al 2010b;Sun et al 2010;Close et al 2011;Liu et al 2011). The SH2 domains are required for Spt6 to interact with the CTD of Rpb1 of RNAPII, for normal levels of Spt6 recruitment to chromatin in vivo, and for wild-type function (Dengl et al 2009;Diebold et al 2010b;Mayer et al 2010;Sun et al 2010;Close et al 2011;Liu et al 2011).…”

Section: Spt6 and Fact: Factors Controlling Transcriptional Integritymentioning

confidence: 99%

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Chromatin and Transcription in Yeast

2012

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Understanding the mechanisms by which chromatin structure controls eukaryotic transcription has been an intense area of investigation for the past 25 years. Many of the key discoveries that created the foundation for this field came from studies of Saccharomyces cerevisiae, including the discovery of the role of chromatin in transcriptional silencing, as well as the discovery of chromatin-remodeling factors and histone modification activities. Since that time, studies in yeast have continued to contribute in leading ways. This review article summarizes the large body of yeast studies in this field.

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Section: Spt6 and Fact: Factors Controlling Transcriptional Integritymentioning

confidence: 99%

Section: Spt6 and Fact: Factors Controlling Transcriptional Integritymentioning

confidence: 99%

Chromatin and Transcription in Yeast

2012

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“…7A). Since the tSH2 domain interacts with the phosphorylated CTD (24)(25)(26), deleting this domain should diminish CTD-dependent Spt6 recruitment. In agreement with a previous study (22), deleting the tSH2 greatly reduced Spt6 but not Pol II (Rpb3) occupancy in the ARG1, ADH1, and PMA1 coding regions ( Fig.…”

Section: Fig 4 Hdacs Promote Spt6 Recruitment To the Coding Regions mentioning

confidence: 99%

“…It possesses a tandem Src homology 2 domain (tSH2) that interacts with phosphorylated Pol II C-terminal domain (CTD) peptides in vitro and is required for full recruitment of Spt6 in vivo (22)(23)(24)(25)(26). Although these observations suggest that CTD phosphorylation is needed for Spt6 recruitment, the role of CTD phosphorylation in vivo in this process is not fully understood.…”

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confidence: 99%

Histone Deacetylases and Phosphorylated Polymerase II C-Terminal Domain Recruit Spt6 for Cotranscriptional Histone Reassembly

Burugula

Jeronimo

Pathak

et al. 2014

Molecular and Cellular Biology

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Spt6 is a multifunctional histone chaperone involved in the maintenance of chromatin structure during elongation by RNA polymerase II (Pol II). Spt6 has a tandem SH2 (tSH2) domain within its C terminus that recognizes Pol II C-terminal domain (CTD) peptides phosphorylated on Ser2, Ser5, or Try1 in vitro. Deleting the tSH2 domain, however, only has a partial effect on Spt6 occupancy in vivo, suggesting that more complex mechanisms are involved in the Spt6 recruitment. Our results show that the Ser2 kinases Bur1 and Ctk1, but not the Ser5 kinase Kin28, cooperate in recruiting Spt6, genomewide. Interestingly, the Ser2 kinases promote the association of Spt6 in early transcribed regions and not toward the 3= ends of genes, where phosphorylated Ser2 reaches its maximum level. In addition, our results uncover an unexpected role for histone deacetylases (Rpd3 and Hos2) in promoting Spt6 interaction with elongating Pol II. Finally, our data suggest that phosphorylation of the Pol II CTD on Tyr1 promotes the association of Spt6 with the 3= ends of transcribed genes, independently of Ser2 phosphorylation. Collectively, our results show that a complex network of interactions, involving the Spt6 tSH2 domain, CTD phosphorylation, and histone deacetylases, coordinate the recruitment of Spt6 to transcribed genes in vivo. D ynamic reorganization of chromatin structure is important for the regulation of transcription by RNA polymerase II (Pol II). Several ATP-dependent chromatin remodelers, histone-modifying enzymes, and histone chaperones promote the disruption of chromatin structure to allow transcription by Pol II and to restore chromatin structure in the wake of transcription (1, 2). Spt6 is a highly conserved and multifunctional protein shown to regulate multiple steps of transcription, including initiation (3, 4) and elongation (5, 6). In addition, it is important for other DNAdependent processes such as recombination (7,8), mRNA export (9), and viral replication (10).Spt6 interacts with histones H3 and H4 (11) and functions as a histone chaperone to regulate cotranscriptional nucleosome reassembly and to modulate chromatin structure, including histone modifications (11-15). Depletion of Spt6 in yeast (Saccharomyces cerevisiae) causes a widespread reduction in histone H3 primarily from the 5= ends of transcribed genes, indicating the importance of Spt6 in maintaining histone occupancy (16). One of the effects of losing Spt6 function is altered gene expression and activation of intragenic cryptic transcription (17-19). Aberrant transcription is also associated with histone deacetylase (HDAC) mutants. Impairing the function of the HDAC Rpd3-small (Rpd3S) and Hos2-Set3 complexes leads to cryptic and antisense transcription genome-wide (20, 21). It is not clear whether Spt6 and HDACs collaborate to suppress spurious transcription.Spt6 localization to transcribed regions strongly correlates with Pol II occupancy (15,22). It possesses a tandem Src homology 2 domain (tSH2) that interacts with phosphorylated Pol II C-terminal doma...

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“…Therefore, the structural investigation of this unusual SH2 domain should increase our understanding of the interaction of this SH2 domain with RNAPII CTD. Recently, three groups reported the crystal structures of two tandem SH2 domains of Saccharomyces cerevisiae, Candida glabrata, and Antonospora locustae Spt6 (22)(23)(24). They found that the tandem SH2 domains directly bound to Ser 2 -phosphorylated RNAPII CTD, and both SH2 domains were essential for Spt6 function in vivo.…”

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confidence: 99%