Transcriptional Regulation by Lge1p Requires a Function Independent of Its Role in Histone H2B Ubiquitination

Zhang, Xiaoting; Kolaczkowska, Ania; Devaux, Frédéric; Panwar, Sneh Lata; Hallstrom, Timothy C.; Jacq, Claude; Moye‐Rowley, W. Scott

doi:10.1074/jbc.m408333200

Cited by 34 publications

(46 citation statements)

References 61 publications

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“…Indeed, as previously reported, we found that rad6⌬ and bre1⌬ strains and strains in which the histone H2B ubiquitylation site is mutated (htb1-K123R) exhibited ARG1 derepression ( Fig. 4A and B) (26,38,48,73,84). Note that rad6⌬ cells exhibited higher levels of ARG1 derepression than either bre1⌬ or htb1-K123R strains.…”

Section: Resultssupporting

confidence: 66%

“…Deletion of RAD6, mutation of the Rad6 ubiquitin conjugation site, or mutation of histone H2B K123 results in derepression of an ARG1-lacZ reporter construct (73). Consistent with these observations, both gene-specific and genome-wide studies found increased ARG1 expression in htb1-K123R cells (38,48,84). Therefore, it is possible that the Paf1 complex may promote transcriptional activation and repression through the very same histone modifications.…”

supporting

confidence: 70%

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The Paf1 Complex Represses ARG1 Transcription in Saccharomyces cerevisiae by Promoting Histone Modifications

Crisucci

Arndt

2011

Eukaryot Cell

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The conserved multifunctional Paf1 complex is important for the proper transcription of numerous genes, and yet the exact mechanisms by which it controls gene expression remain unclear. While previous studies indicate that the Paf1 complex is a positive regulator of transcription, the repression of many genes also requires the Paf1 complex. In this study we used ARG1 as a model gene to study transcriptional repression by the Paf1 complex in Saccharomyces cerevisiae. We found that several members of the Paf1 complex contribute to ARG1 repression and that the complex localizes to the ARG1 promoter and coding region in repressing conditions, which is consistent with a direct repressive function. Furthermore, Paf1 complex-dependent histone modifications are enriched at the ARG1 locus in repressing conditions, and histone H3 lysine 4 methylation contributes to ARG1 repression. Consistent with previous reports, histone H2B monoubiquitylation, the mark upstream of histone H3 lysine 4 methylation, is also important for ARG1 repression. To begin to identify the mechanistic basis for Paf1 complex-mediated repression of ARG1, we focused on the Rtf1 subunit of the complex. Through an analysis of RTF1 mutations that abrogate known Rtf1 activities, we found that Rtf1 mediates ARG1 repression primarily by facilitating histone modifications. Other members of the Paf1 complex, such as Paf1, appear to repress ARG1 through additional mechanisms. Together, our results suggest that Rtf1-dependent histone H2B ubiquitylation and H3 K4 methylation repress ARG1 expression and that histone modifications normally associated with active transcription can occur at repressed loci and contribute to transcriptional repression.The organization of eukaryotic DNA into chromatin presents a significant obstacle to transcription by RNA polymerase II (Pol II). To allow proper gene expression, a multitude of accessory factors associate with RNA Pol II to facilitate the transcription of a chromatin template. A conserved, multifunctional protein complex that enables proper RNA Pol II transcription is the Paf1 complex. In Saccharomyces cerevisiae, the Paf1 complex consists of Paf1, Ctr9, Cdc73, Rtf1, and Leo1 (36,45,64,66). Many physical and genetic interactions and phenotypes implicate the Paf1 complex in regulating the elongation stage of transcription. Specifically, strains lacking Paf1 complex members exhibit phenotypes associated with transcription elongation defects, such as sensitivity to 6-azauracil and mycophenolic acid (12, 66). During transcription elongation, the Paf1 complex associates with RNA Pol II on open reading frames (ORFs) (36, 54), where it orchestrates modifications to the chromatin template (11,35,49,50,78) and influences the phosphorylation state of the RNA Pol II carboxy-terminal domain (CTD) (46, 51). In addition, the Paf1 complex genetically and physically interacts with elongation factors such as the Spt4-Spt5 (yDSIF) and Spt16-Pob3 (yFACT) complexes, suggesting coordinated functions of these elongation factors during transc...

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Section: Resultssupporting

confidence: 66%

supporting

confidence: 70%

The Paf1 Complex Represses ARG1 Transcription in Saccharomyces cerevisiae by Promoting Histone Modifications

Crisucci

Arndt

2011

Eukaryot Cell

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“…Two genes were identified that, when deleted, conferred resistance to YNG1 overexpression: YLR177w and LGE1. The function of YLR177w is unknown, but LGE1 is required for RAD6-dependent ubiquitination of histone H2B and is also involved in regulating gene expression in a pathway independent of RAD6 (25,33,66). To determine whether the requirement of LGE1 for Yng1p toxicity was dependent on H2B ubiquitination, we sought to determine whether rad6⌬ strains also showed resistance.…”

Section: Yng1p Interacts With the Histone H3 Tail In Vivomentioning

confidence: 99%

The Yng1p Plant Homeodomain Finger Is a Methyl-Histone Binding Module That Recognizes Lysine 4-Methylated Histone H3

Martin¹,

Baetz

Shi

et al. 2006

Molecular and Cellular Biology

142

113

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The ING (inhibitor of growth) protein family includes a group of homologous nuclear proteins that share a highly conserved plant homeodomain (PHD) finger domain at their carboxyl termini. Members of this family are found in multiprotein complexes that posttranslationally modify histones, suggesting that these proteins serve a general role in permitting various enzymatic activities to interact with nucleosomes. There are three members of the ING family in Saccharomyces cerevisiae: Yng1p, Yng2p, and Pho23p. Yng1p is a component of the NuA3 histone acetyltransferase complex and is required for the interaction of NuA3 with chromatin. To gain insight into the function of the ING proteins, we made use of a genetic strategy to identify genes required for the binding of Yng1p to histones. Using the toxicity of YNG1 overexpression as a tool, we showed that Yng1p interacts with the amino-terminal tail of histone H3 and that this interaction can be disrupted by loss of lysine 4 methylation within this tail. Additionally, we mapped the region of Yng1p required for overexpression of toxicity to the PHD finger, showed that this region capable of binding lysine 4-methylated histone H3 in vitro, and demonstrated that mutations of the PHD finger that abolish binding in vitro are no longer toxic in vivo. These results identify a novel function for the Yng1p PHD finger in promoting stabilization of the NuA3 complex at chromatin through recognition of histone H3 lysine 4 methylation.Chromatin structure can be regulated by the addition of posttranslational modifications to histones, including acetylation, methylation, phosphorylation, and ubiquitination. These modifications are thought to function by creating docking sites for factors which alter chromatin structure (27,58). Consistent with this, several protein motifs have been identified that mediate the selective interaction of transcription-regulating complexes with specific histone modifications. The first such identified motif is the bromodomain, which preferentially interacts with acetylated histones (7,10,24,49,50,65). Bromodomains are found in a number of protein complexes, including components of the basal transcription machinery and chromatin remodeling complexes (20, 41), which may explain, in part, how histone acetylation can facilitate transcription. Bromodomains are also found in a number of histone methyltransferases, suggesting that histone acetylation can mediate histone methylation (6). The ability of one histone modification to recruit another histone-modifying enzyme is a common recurring theme in chromatin research.A second motif which has been shown to bind modified histones is the chromodomain, which preferentially interacts with methylated lysines (19,52). Chromodomains are found in proteins involved in both the activation and silencing of transcription, consistent with the role of histone methylation in both events (31). Similar to bromodomains, chromodomains are found in chromatin remodeling complexes, histone acetyltransferases, and histone methyltransfer...

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“…These binding sites will be referred to as metal-response elements (MREs). This construct has been previously characterized and confers copper-regulated Pdr3p production on cells (18). This plasmid will be referred to as MRE-HA-Pdr3p and was constructed in the low copy number vector pRS315 backbone, which served as a control for this analysis.…”

Section: Ssa1p Interacts Preferentially With Pdr3p In Vivo-mentioning

confidence: 99%

“…1 To whom correspondence should be addressed: Dept. of Molecular Physiology and Biophysics, 6- levels of this protein are maintained at an extremely low level in ϩ cells (18). PDR3 transcription is strongly induced in 0 mutants, and this autoregulation is required for normal development of multidrug resistance in these cells.…”

mentioning

confidence: 99%

Negative Transcriptional Regulation of Multidrug Resistance Gene Expression by an Hsp70 Protein

Shahi

Gulshan

Moye‐Rowley

2007

Journal of Biological Chemistry

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One of the most common origins of multidrug resistance occurs via the overproduction of ATP-binding cassette (ABC) transporter proteins. These ABC transporters then act as broad specificity drug pumps and efflux a wide range of toxic agents out of the cell. The yeast Saccharomyces cerevisiae exhibits multiple or pleiotropic drug resistance (Pdr) often through the overproduction of a plasma membrane-localized ABC transporter protein called Pdr5p. Expression of the PDR5 gene is controlled by two zinc cluster-containing transcription factors called Pdr1p and Pdr3p. Cells that lack their mitochondrial genome ( 0 cells) strongly induce PDR5 transcription in a Pdr3p-dependent fashion. To identify proteins associated with Pdr3p that might act to regulate this factor, a tandem affinity purification (TAP) moiety was fused to Pdr3p, and this recombinant protein was purified from yeast cells. The same similarities to mammalian cells that have made yeast a powerful model eukaryotic organism restrict the ability to design antifungal drugs without also impacting the health of the animal host. This has led to a limited repertoire of antifungal drugs and makes the development of drug-resistant fungi a special burden on chemotherapy of infections by these organisms. Even more serious is the acquisition of fungi with a multidrug resistance phenotype that can permit tolerance to many antifungal agents with a single genetic change (reviewed in Ref. 1). Saccharomyces cerevisiae mutant strains with a single nuclear mutation have been isolated which enable these mutants to become tolerant of a wide range of toxic compounds. These mutant cells are referred to as having a pleiotropic drug resistant (Pdr) 2 phenotype (reviewed in Ref.2). Mutations either within genes encoding transcriptional regulators of PDR genes or in their regulatory inputs led to overexpression of downstream transporter proteins with associated multidrug resistance. The most extensively studied gene contributing to this pathway in S. cerevisiae is PDR5, which encodes an ATPbinding cassette (ABC) transporter that exhibits broad spectrum drug efflux activity (3-5). Transcription of PDR5 and other Pdr pathway genes are controlled in large measure by the Zn(II) 2 Cys 6 zinc finger regulators Pdr1p and Pdr3p (reviewed in Refs. 6 and 7).Substitution mutant forms of Pdr1p and Pdr3p transcription factors have been identified that lead to high level overexpression of Pdr5p with an associated increase in multidrug resistance (8 -10). Genetic experiments indicate that these mutant transcription factors behave as dominant, hyperactive forms of the regulatory proteins. Pdr1p and Pdr3p share partially overlapping function and control expression of their target genes by binding to a sequence element referred to as the Pdr1p/Pdr3p response element (PDRE) (11,12). The PDR3 gene itself is also controlled by two PDREs in its promoter and involves an autoregulatory loop (13). The relative ease of isolation of these hyperactive transcription factors led to the suggestion that both Pdr1p...

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Transcriptional Regulation by Lge1p Requires a Function Independent of Its Role in Histone H2B Ubiquitination

Cited by 34 publications

References 61 publications

The Paf1 Complex Represses ARG1 Transcription in Saccharomyces cerevisiae by Promoting Histone Modifications

The Paf1 Complex Represses ARG1 Transcription in Saccharomyces cerevisiae by Promoting Histone Modifications

The Yng1p Plant Homeodomain Finger Is a Methyl-Histone Binding Module That Recognizes Lysine 4-Methylated Histone H3

Negative Transcriptional Regulation of Multidrug Resistance Gene Expression by an Hsp70 Protein

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