Insights into the structure and architecture of the CCR4â€“NOT complex

Xu, Kun; Bai, Yujia; Zhang, Aili; Zhang, Qionglin; Bartlam, Mark

doi:10.3389/fgene.2014.00137

Cited by 40 publications

(47 citation statements)

References 70 publications

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“…It can catalyze deadenylation in both gene- and context-specific manners to allow control of poly(A) tail lengths (Collart and Panasenko, 2012, Shirai et al., 2014, Xu et al., 2014). It has been proposed that different RNA binding proteins and/or different subunits in the Ccr4-Not complex may mediate the recruitment and regulation of different target mRNAs.…”

Section: Discussionmentioning

confidence: 99%

“…Ccr4-Not is the main mRNA deadenylase complex in eukaryotic cells that shortens mRNA poly(A) tails (Collart and Panasenko, 2012, Shirai et al., 2014, Xu et al., 2014). It has been implicated in various physiological and developmental processes, such as spermatogenesis (Berthet et al., 2004), heart development (Neely et al., 2010), energy metabolism (Morita et al., 2011), B cell differentiation (Inoue et al., 2015), osteoporosis (Watanabe et al., 2014), reprogramming (Kamon et al., 2014), and ESC self-renewal (Hu et al., 2009, Zheng et al., 2012).…”

Section: Introductionmentioning

confidence: 99%

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CNOT3-Dependent mRNA Deadenylation Safeguards the Pluripotent State

et al. 2016

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SummaryPoly(A) tail length and mRNA deadenylation play important roles in gene regulation. However, how they regulate embryonic development and pluripotent cell fate is not fully understood. Here we present evidence that CNOT3-dependent mRNA deadenylation governs the pluripotent state. We show that CNOT3, a component of the Ccr4-Not deadenylase complex, is required for mouse epiblast maintenance. It is highly expressed in blastocysts and its deletion leads to peri-implantation lethality. The epiblast cells in Cnot3 deletion embryos are quickly lost during diapause and fail to outgrow in culture. Mechanistically, CNOT3 C terminus is required for its interaction with the complex and its function in embryonic stem cells (ESCs). Furthermore, Cnot3 deletion results in increases in the poly(A) tail lengths, half-lives, and steady-state levels of differentiation gene mRNAs. The half-lives of CNOT3 target mRNAs are shorter in ESCs and become longer during normal differentiation. Together, we propose that CNOT3 maintains the pluripotent state by promoting differentiation gene mRNA deadenylation and degradation, and we identify poly(A) tail-length regulation as a post-transcriptional mechanism that controls pluripotency.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

CNOT3-Dependent mRNA Deadenylation Safeguards the Pluripotent State

et al. 2016

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“…This large complex is composed of nine core subunits with roles in regulation of transcription, mRNA export, and mRNA decay (Lau et al 2009;Collart and Panasenko 2012;Doidge et al 2012;Miller and Reese 2012;Temme et al 2014;Xu et al 2014). The major component of CCR4-NOT is the 250 kDa NOT1 protein, which acts as a scaffold for the multisubunit complex (Nasertorabi et al 2011;Petit et al 2012;Bawankar et al 2013).…”

Section: Introductionmentioning

confidence: 99%

Xenopus CAF1 requires NOT1-mediated interaction with 4E-T to repress translation in vivo

Waghray

Williams

Coon

et al. 2015

RNA

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RNA-regulatory factors bound to 3 ′ UTRs control translation and stability. Repression often is associated with poly(A) removal. The deadenylase CAF1 is a core component of the CCR4-NOT complex. Our prior studies established that CAF1 represses translation independent of deadenylation. We sought the mechanism of its deadenylation-independent repression in Xenopus oocytes. Our data reveal a chain of interacting proteins that links CAF1 to CCR4-NOT and to Xp54 and 4E-T. Association of CAF1 with NOT1, the major subunit of CCR4-NOT, is required for repression by CAF1 tethered to a reporter mRNA. Affinity purification-mass spectrometry and coimmunoprecipitation revealed that at least five members of the CCR4-NOT complex were recruited by CAF1. The recruitment of these proteins required NOT1, as did the ability of tethered CAF1 to repress translation. In turn, NOT1 was needed to recruit Xp54 and 4E-T. We examined the role of 4E-T in repression using mutations that disrupted either eIF4E-dependent or -independent mechanisms. Expression of a 4E-T truncation that still bound eIF4E alleviated repression by tethered CAF1, NOT1, and Xp54. In contrast, a mutant 4E-T that failed to bind eIF4E did not. Repression of global translation was affected only by the eIF4E-dependent mechanism. Reporters bearing IRES elements revealed that repression via tethered CAF1 and Xp54 is cap-and eIF4E-independent, but requires one or more of eIF4A, eIF4B, and eIF4G. We propose that RNA-binding proteins, and perhaps miRNAs, repress translation through an analogous chain of interactions that begin with the 3 ′ UTR-bound repressor and end with the noncanonical activity of 4E-T.

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“…This step is thought to involve the recruitment of 3’–5’-exonucleases, or deadenylases, possibly through recruitment of the NOT1 scaffolding protein to the extreme C-terminus of the proteins [12, 13]. NOT1 in turn is bound to at least two deadenylases [14], and its binding to the C-terminus of TTP family proteins may at least partially explain the ability of the proteins to promote mRNA deadenylation and decay (Fig. 1).…”

Section: The Ttp Family Of Rna Binding Proteinsmentioning

confidence: 99%

Tristetraprolin as a Therapeutic Target in Inflammatory Disease

Patial

Blackshear

2016

Trends in Pharmacological Sciences

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Members of the tristetraprolin (TTP) family of RNA binding proteins are found in all major eukaryotic groups. Family members from plants through humans can bind AU-rich elements in target mRNAs with high affinity. In mammalian cells, these proteins then promote deadenylation and decay of target transcripts. Four such proteins are found in the mouse, of which the best studied is TTP. When its gene is disrupted in the mouse, the animals develop a severe syndrome of arthritis, autoimmunity, cachexia, dermatitis, and myeloid hyperplasia. Conversely, recent overexpression studies have demonstrated protection against several experimental models of immune inflammatory disease. This endogenous anti-inflammatory protein could serve as the basis for novel approaches to therapy of similar conditions in humans.

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Insights into the structure and architecture of the CCR4â€“NOT complex

Cited by 40 publications

References 70 publications

CNOT3-Dependent mRNA Deadenylation Safeguards the Pluripotent State

CNOT3-Dependent mRNA Deadenylation Safeguards the Pluripotent State

Xenopus CAF1 requires NOT1-mediated interaction with 4E-T to repress translation in vivo

Tristetraprolin as a Therapeutic Target in Inflammatory Disease

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