Ccr4-Not complex: the control freak of eukaryotic cells

Miller, Jason E.; Reese, Joseph C.

doi:10.3109/10409238.2012.667214

Cited by 166 publications

(204 citation statements)

References 167 publications

(315 reference statements)

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“…In this case, transcript-specific targeting of CNOT2 would rely combinatorially on its promoter-specific recruitment by TFs and RBP-dependent loading onto the transcribing mRNA. It is also notable that the coordinated functions of CCR4-NOT in transcription and mRNA decay rely more specifically on its NOT2-NOT3 module, which interacts with ERG 11 .…”

Section: Discussionmentioning

confidence: 99%

The transcription factor ERG recruits CCR4–NOT to control mRNA decay and mitotic progression

Rambout

Detiffe

Bruyr

et al. 2016

Nat Struct Mol Biol

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nature structural & molecular biology advance online publication a r t i c l e sAlthough undisputable evidence has clearly demonstrated that the nuclear steps of mRNA processing are mechanistically linked to transcription, a conceptual evolution in gene regulation has come with the realization that transcription might also be functionally connected to more remote processes occurring in the cytoplasm, such as mRNA decay 1,2 . Cytoplasmic mRNA decay is initiated by deadenylation, a rate-limiting event during which the poly(A) tail of the transcript is trimmed off by the CCR4-NOT complex, the main deadenylation machinery in eukaryotes 3 . The degradation of specific mRNAs, a key process in the regulation of eukaryotic gene expression, is achieved through the recruitment of the CCR4-NOT complex by sequence-specific RNA-binding proteins (RBPs) or by the microRNA machinery 3,4 . Poly(A)-shortened mRNAs, along with factors involved in the deadenylation, decapping and mRNA-degradation machineries, accumulate in microscopic mRNA-protein complex (mRNP) aggregates called processing bodies (PBs) 5 .The idea of coupling between mRNA synthesis and degradation has recently emerged. Genome-wide expression studies in yeast have shown that mRNA synthesis and decay are mechanistically and functionally coordinated, thus supporting the existence of common molecular effectors [6][7][8][9] . In particular, the CCR4-NOT deadenylation complex was first described as a transcriptional regulator and has been implicated in initiation and elongation by RNA polymerase II 10,11 . More surprisingly, it has also been shown that degradation of yeast mRNAs is determined by cis-acting sequence elements in promoters 12,13 . These findings have led to the concept of mRNA imprinting, in which sequence-specific DNA-binding factors might orchestrate mRNA synthesis and decay. This decay would occur via loading of factors regulating cytoplasmic mRNA degradation onto the transcribing mRNA 14 . However, the identity of these DNA-binding mRNA coordinators is still obscure, and it remains to be tested whether such coupling between transcription and decay also exists in higher eukaryotes. E26 (Ets) proteins, a family of 28 helix-loop-helix transcription factors (TFs) in metazoans, are characterized by a highly conserved DNA-binding ETS domain 15 . Through this domain, Ets factors bind specific gene promoters and act as key regulators in many biological processes including cellular proliferation, apoptosis, differentiation and survival 16 . ERG, FLI1 and the more structurally divergent FEV compose the Erg subfamily of Ets factors and have been identified as driving factors in prostate cancer, Ewing's tumors and leukemias 15,17 . Using ERG as a paradigm, we sought to investigate the possibility that eukaryotic transcription factors might be directly involved in cytoplasmic mRNA decay. We demonstrate that ERG triggers degradation of mRNAs connected to Aurora signaling by recruiting RBPs and the CCR4-NOT deadenylation complex and that this activity is important fo...

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Section: Discussionmentioning

confidence: 99%

The transcription factor ERG recruits CCR4–NOT to control mRNA decay and mitotic progression

Rambout

Detiffe

Bruyr

et al. 2016

Nat Struct Mol Biol

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“…This process is carried out by Pan2/3 and Ccr4 in yeast, with Ccr4 appearing to play the major role (9 -11). Ccr4 resides in a multisubunit complex called Ccr4-Not, which was first described as a transcriptional activator/ repressor (9,12). In addition to regulating the TATA-binding protein at the initiation stage, it directly associates with elongating RNA polymerase II (RNAPII) 2 and can reactivate arrested polymerase in vitro (13,14).…”

mentioning

confidence: 99%

The Rpb4/7 Module of RNA Polymerase II Is Required for Carbon Catabolite Repressor Protein 4-Negative on TATA (Ccr4-Not) Complex to Promote Elongation

Babbarwal

Reese

2014

Journal of Biological Chemistry

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Background: mRNA transcription and decay are coordinated processes. Results: The Rpb4/7 module of RNA polymerase II is required for the transcription and mRNA decay factor Ccr4-Not to associate with elongation complexes. Conclusion: Association between these two entities is required for Ccr4-Not to promote transcription elongation. Significance: Our work provides molecular insights into how transcription and mRNA decay are linked.

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“…The mammalian CCR4-NOT complex consists of multiple modules involved in transcription (CNOT2/ CNOT3), mRNA degradation (CNOT6/CNOT6L/ CNOT7/CNOT8), and protein quality control (CNOT4) (for review, see Miller and Reese 2012). We found that EBF1 interacts specifically with the CNOT3 subunit of the complex.…”

Section: Discussionmentioning

confidence: 93%

“…The CCR4-NOT complex is assembled around the CNOT1 subunit, which serves as a scaffold and interacts with various modules. The CNOT2 and CNOT3 subunits together form a module engaged in gene transcription and RNA targeting, whereas CNOT6, CNOT6L, CNOT7, and CNOT8 form a "deadenylase module" involved in mRNA degradation (for review, see Miller and Reese 2012;Collart et al 2013). In addition, CNOT4 represents a module for protein quality control that is not a constitutive component of the complex (Lau et al 2009;Bhaskar et al 2015).…”

mentioning

confidence: 99%

“…The CCR4-NOT complex is a 1.2-to 1.9-MDa multisubunit complex that is found in both the nucleus and cytoplasm and has been shown to play a role in gene transcription, mRNA degradation, and quality control during protein synthesis (for review, see Miller and Reese 2012;Collart et al 2013). CCR4/NOT was initially identified as a transcriptional regulator (Collart and Struhl 1994;Liu et al 1998;Zwartjes et al 2004) and subsequently as a cytoplasmic deadenylase that shortens the poly(A) tail of mRNA (Tucker et al 2001;Chen et al 2002).…”

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confidence: 99%

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Interaction of CCR4–NOT with EBF1 regulates gene-specific transcription and mRNA stability in B lymphopoiesis

et al. 2016

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Transcription factor EBF1 (early B-cell factor 1) regulates early B-cell differentiation by poising or activating lineagespecific genes and repressing genes associated with alternative cell fates. To identify proteins that regulate the diverse functions of EBF1, we used SILAC (stable isotope labeling by amino acids in cell culture)-based mass spectrometry of proteins associated with endogenous EBF1 in pro-B cells. This analysis identified most components of the multifunctional CCR4-NOT complex, which regulates transcription and mRNA degradation. CNOT3 interacts with EBF1, and we identified histidine 240 in EBF1 as a critical residue for this interaction. Complementation of Ebf1 −/− progenitors with EBF1H240A revealed a partial block of pro-B-cell differentiation and altered expression of specific EBF1 target genes that show either reduced transcription or increased mRNA stability. Most deregulated EBF1 target genes show normal occupancy by EBF1H240A, but we also detected genes with altered occupancy, suggesting that the CCR4-NOT complex affects multiple activities of EBF1. Mice with conditional Cnot3 inactivation recapitulate the block of early B-cell differentiation, which we found to be associated with an impaired autoregulation of Ebf1 and reduced expression of pre-B-cell receptor components. Thus, the interaction of the CCR4-NOT complex with EBF1 diversifies the function of EBF1 in a context-dependent manner and may coordinate transcriptional and post-transcriptional gene regulation.

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Ccr4-Not complex: the control freak of eukaryotic cells

Cited by 166 publications

References 167 publications

The transcription factor ERG recruits CCR4–NOT to control mRNA decay and mitotic progression

The transcription factor ERG recruits CCR4–NOT to control mRNA decay and mitotic progression

The Rpb4/7 Module of RNA Polymerase II Is Required for Carbon Catabolite Repressor Protein 4-Negative on TATA (Ccr4-Not) Complex to Promote Elongation

Interaction of CCR4–NOT with EBF1 regulates gene-specific transcription and mRNA stability in B lymphopoiesis

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