Modulation of Ubc4p/Ubc5p-Mediated Stress Responses by the RING-Finger-Dependent Ubiquitin-Protein Ligase Not4p in <i>Saccharomyces cerevisiae</i>

Mulder, Klaas W.; Inagaki, Akiko; Cameroni, Elisabetta; Mousson, Florence; Winkler, G. Sebastiaan; Virgilio, Claudio De; Collart, Martine A.; Timmers, H. Th. Marc

doi:10.1534/genetics.106.060640

Cited by 50 publications

(93 citation statements)

References 49 publications

(66 reference statements)

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“…Rbp1 is predominantly hypophosphorylated (Suh et al 2005; data not shown). All of the known core subunits of the Ccr4-Not complex were detected in the TAP purification, and its composition matched that published by others (Mulder et al 2007b;Azzouz et al 2009). We assembled radiolabeled elongation complexes (EC70) on a tailed template, as described previously ) and illustrated in Figure 3B.…”

Section: Ccr4-not Directly Binds To Rnapii Elongation Complexessupporting

confidence: 84%

The multifunctional Ccr4–Not complex directly promotes transcription elongation

Kruk¹,

Dutta²,

Fu³

et al. 2011

Genes Dev.

158

228

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The Ccr4-Not complex has been implicated in the control of multiple steps of mRNA metabolism; however, its functions in transcription remain ambiguous. The discovery that Ccr4/Pop2 is the major cytoplasmic mRNA deadenylase and the detection of Not proteins within mRNA processing bodies have raised questions about the roles of the Ccr4-Not complex in transcription. Here we firmly establish Ccr4-Not as a positive elongation factor for RNA polymerase II (RNAPII). The Ccr4-Not complex is targeted to the coding region of genes in a transcription-dependent manner similar to RNAPII and promotes elongation in vivo. Furthermore, Ccr4-Not interacts directly with elongating RNAPII complexes and stimulates transcription elongation of arrested polymerase in vitro. Ccr4-Not can reactivate backtracked RNAPII using a mechanism different from that of the well-characterized elongation factor TFIIS. While not essential for its interaction with elongation complexes, Ccr4-Not interacts with the emerging transcript and promotes elongation in a manner dependent on transcript length, although this interaction is not required for it to bind RNAPII. Our comprehensive analysis shows that Ccr4-Not directly regulates transcription, and suggests it does so by promoting the resumption of elongation of arrested RNAPII when it encounters transcriptional blocks in vivo.

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Section: Ccr4-not Directly Binds To Rnapii Elongation Complexessupporting

confidence: 84%

The multifunctional Ccr4–Not complex directly promotes transcription elongation

Kruk¹,

Dutta²,

Fu³

et al. 2011

Genes Dev.

158

228

View full text Add to dashboard Cite

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“…Here we asked whether the CCCH and RING zinc-finger domains (which are proposed to regulate RNA splicing and ubiquitylation, respectively) have specific roles in either of these two phenotypes. We generated fly lines expressing different Mdlc domains under UAS control: full- ), which is reported to interfere with E2/E3 interactions in RING domain-containing E3 ubiquitin ligases (Mulder et al, 2007); and Mdlc lacking both zinc fingers (Mdlc ΔCCCH+RING ). In addition, we generated a transgene expressing the full-length human ortholog of Mdlc (RNF113A).…”

Section: Mdlc Zinc-finger Deletions Reveal Different Requirements Formentioning

confidence: 99%

midlife crisisencodes a conserved zinc-finger protein required to maintain neuronal differentiation inDrosophila

2013

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SUMMARYStem cells generate progeny that undergo terminal differentiation. The initiation and maintenance of the differentiated status is crucial for tissue development, function and homeostasis. Drosophila neural stem cells (neuroblasts) are a model for stem cell selfrenewal and differentiation; they divide asymmetrically to self-renew and generate the neurons and glia of the CNS. Here we report the identification of midlife crisis (mdlc; CG4973) as a gene required for the maintenance of neuronal differentiation and for neuroblast proliferation in Drosophila. mdlc encodes a ubiquitously expressed zinc-finger-containing protein with conserved orthologs from yeast to humans that are reported to have a role in RNA splicing. Using clonal analysis, we demonstrate that mdlc mutant neurons initiate but fail to complete differentiation, as judged by the loss of the pro-differentiation transcription factor Prospero, followed by derepression of the neuroblast factors Deadpan, Asense and Cyclin E. RNA-seq shows that loss of Mdlc decreases pros transcript levels and results in aberrant pros splicing. Importantly, misexpression of the full-length human ortholog, RNF113A, completely rescues all CNS defects in mdlc mutants. We conclude that Mdlc plays an essential role in maintaining neuronal differentiation, raising the possibility that RNF113A regulates neuronal differentiation in the human CNS.

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“…Not4 is one of the subunits of the CCR4/NOT complex, a multifunctional complex that has been implicated in transcriptional regulation and RNA deadenylation (Collart and Struhl 1994;Denis et al 2001;Collart 2003;Collart and Timmers 2004;Mulder et al 2007b). Although the precise role played by Not4 in the CCR4/ NOT complex remains to be determined, Not4 has been shown to have both positive and negative roles in transcriptional regulation and a positive role in transcriptional elongation (Collart 2003).…”

mentioning

confidence: 99%

“…Although the precise role played by Not4 in the CCR4/ NOT complex remains to be determined, Not4 has been shown to have both positive and negative roles in transcriptional regulation and a positive role in transcriptional elongation (Collart 2003). In addition, the RING finger domain of yeast Not4 has been shown to be important for the induction of the ribonucleotide reductase (RNR) gene family in response to DNA damage via MMS and hydroxyurea and for E3 ubiquitin ligase activity (Mulder et al 2007b). Until now, the mechanism by which Not4's RING finger domain acts to modulate histone H3 K4 methylation has been unclear and contradictory (Laribee et al 2007;Mulder et al 2007a).…”

mentioning

confidence: 99%

Polyubiquitination of the demethylase Jhd2 controls histone methylation and gene expression

Mersman¹,

Du²,

Fingerman³

et al. 2009

Genes Dev.

134

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The identification of histone methyltransferases and demethylases has uncovered a dynamic methylation system needed to modulate appropriate levels of gene expression. Gene expression levels of various histone demethylases, such as the JARID1 family, show distinct patterns of embryonic and adult expression and respond to different environmental cues, suggesting that histone demethylase protein levels must be tightly regulated for proper development. In our study, we show that the protein level of the yeast histone H3 Lys 4 (H3 K4) demethylase Jhd2/ Kdm5 is modulated through polyubiquitination by the E3 ubiquitin ligase Not4 and turnover by the proteasome. We determine that polyubiquitin-mediated degradation of Jhd2 controls in vivo H3 K4 trimethylation and gene expression levels. Finally, we show that human NOT4 can polyubiquitinate human JARID1C/SMCX, a homolog of Jhd2, suggesting that this is likely a conserved mechanism. We propose that Not4 is an E3 ubiquitin ligase that monitors and controls a precise amount of Jhd2 protein so that the proper balance between histone demethylase and histone methyltransferase activities occur in the cell, ensuring appropriate levels of H3 K4 trimethylation and gene expression.[Keywords: Jhd2; chromatin; histone methylation; demethylase; ubiquitination; proteasome] Supplemental material is available at http://www.genesdev.org.

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Modulation of Ubc4p/Ubc5p-Mediated Stress Responses by the RING-Finger-Dependent Ubiquitin-Protein Ligase Not4p in Saccharomyces cerevisiae

Cited by 50 publications

References 49 publications

The multifunctional Ccr4–Not complex directly promotes transcription elongation

The multifunctional Ccr4–Not complex directly promotes transcription elongation

midlife crisisencodes a conserved zinc-finger protein required to maintain neuronal differentiation inDrosophila

Polyubiquitination of the demethylase Jhd2 controls histone methylation and gene expression

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