Human Ccr4–Not complexes contain variable deadenylase subunits

Lau, Nga-Chi; Kolkman, Annemieke; Schaik, F.M.A. van; Mulder, Klaas W.; Pijnappel, W.W.M. Pim; Heck, Albert J. R.; Timmers, H. Th. Marc

doi:10.1042/bj20090500

Cited by 174 publications

(255 citation statements)

References 42 publications

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“…The core of the human CCR4-NOT complex consists of six subunits (CNOT1, CNOT2, CNOT3, CNOT9, CNOT10, and CNOT11) and two catalytically active subunits (CCR4 and CAF1). In human cells, there are two alternative paralogs for each catalytic subunit: CCR4a or CCR4b (also known as CNOT6 or CNOT6-L) and CAF1 or POP2 (also known as CNOT7 or CNOT8) (Lau et al 2009). …”

Section: The Smg7 Pc Region Interacts With Pop2mentioning

confidence: 99%

The SMG5–SMG7 heterodimer directly recruits the CCR4–NOT deadenylase complex to mRNAs containing nonsense codons via interaction with POP2

2013

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Nonsense-mediated mRNA decay (NMD) is a eukaryotic quality control mechanism that detects aberrant mRNAs containing nonsense codons and induces their rapid degradation. This degradation is mediated by SMG6, an NMDspecific endonuclease, as well as the SMG5 and SMG7 proteins, which recruit general mRNA decay enzymes. However, it remains unknown which specific decay factors are recruited and whether this recruitment is direct. Here, we show that SMG7 binds directly to POP2, a catalytic subunit of the CCR4-NOT deadenylase complex, and elicits deadenylation-dependent decapping and 59-to-39 decay of NMD targets. Accordingly, a catalytically inactive POP2 mutant partially suppresses NMD in human cells. The SMG7-POP2 interaction is critical for NMD in cells depleted of SMG6, indicating that SMG7 and SMG6 act redundantly to promote the degradation of NMD targets. We further show that UPF1 provides multiple binding sites for decapping factors. These data unveil a missing direct physical link between NMD and the general mRNA decay machinery and indicate that NMD employs diverse and partially redundant mechanisms to ensure robust degradation of aberrant mRNAs.

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Section: The Smg7 Pc Region Interacts With Pop2mentioning

confidence: 99%

The SMG5–SMG7 heterodimer directly recruits the CCR4–NOT deadenylase complex to mRNAs containing nonsense codons via interaction with POP2

2013

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“…Human orthologues of both complexes exist (22). In humans, the CCR4⅐CAF1 complex comprises two subunits with deadenylase activity (CCR4 and CAF1) together with seven other CNOT proteins (23). Human CCR4 and CAF1 each have two different paralogues: CCR4a (CNOT6) and CCR4b (CNOT6L); and CAF1a (CNOT7) and CAF1b (CNOT8).…”

mentioning

confidence: 99%

MAPKAP Kinase 2 Blocks Tristetraprolin-directed mRNA Decay by Inhibiting CAF1 Deadenylase Recruitment

Marchese

Aubareda

Tudor³

et al. 2010

Journal of Biological Chemistry

137

149

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Tristetraprolin (TTP) directs its target AU-rich element (ARE)-containing mRNAs for degradation by promoting removal of the poly(A) tail. The p38 MAPK pathway regulates mRNA stability via the downstream kinase MAPK-activated protein kinase 2 (MAPKAP kinase 2 or MK2), which phosphorylates and prevents the mRNA-destabilizing function of TTP. We show that deadenylation of endogenous ARE-containing tumor necrosis factor mRNA is inhibited by p38 MAPK. To investigate whether phosphorylation of TTP by MK2 regulates TTP-directed deadenylation of ARE-containing mRNAs, we used a cell-free assay that reconstitutes the mechanism in vitro. We find that phosphorylation of Ser-52 and Ser-178 of TTP by MK2 results in inhibition of TTP-directed deadenylation of ARE-containing RNA. The use of 14-3-3 protein antagonists showed that regulation of TTP-directed deadenylation by MK2 is independent of 14-3-3 binding to TTP. To investigate the mechanism whereby TTP promotes deadenylation, it was necessary to identify the deadenylases involved. The carbon catabolite repressor protein (CCR)4⅐CCR4-associated factor (CAF)1 complex was identified as the major source of deadenylase activity in HeLa cells responsible for TTP-directed deadenylation. CAF1a and CAF1b were found to interact with TTP in an RNAindependent fashion. We find that MK2 phosphorylation reduces the ability of TTP to promote deadenylation by inhibiting the recruitment of CAF1 deadenylase in a mechanism that does not involve sequestration of TTP by 14-3-3. Cyclooxygenase-2 mRNA stability is increased in CAF1-depleted cells in which it is no longer p38 MAPK/MK2-regulated.Many mammalian mRNAs contain adenosine/uridine-rich elements (AREs) 3 in their 3Ј-untranslated regions (UTRs) that target mRNAs for rapid degradation. The importance of AREs in regulation of mRNA stability has been demonstrated particularly for mRNAs of the inflammatory response. The p38 MAPK pathway inhibits ARE-mediated decay allowing for dynamic control of the expression of these mRNAs (1-3). p38 MAPK regulates mRNA stability via the downstream kinase MAPKAP kinase 2 (MK2), which phosphorylates (4, 5) and prevents the function (6, 7) of the mRNA-destabilizing ARE-binding protein, tristetraprolin (TTP). We recently showed that dual control of mRNA stability by TTP and the p38 MAPK pathway is a general mechanism, which operates for many mRNAs of the inflammatory response (8). The importance of TTP in the control of inflammatory gene expression is demonstrated by spontaneous inflammatory arthritis in TTP Ϫ/Ϫ mice arising mainly from increased tumor necrosis factor (TNF) production (9). p38 MAPK also regulates mRNA stability by direct phosphorylation and inactivation of another ARE-binding protein, KH domain-splicing regulatory protein (10, 11). p38 MAPK inhibitors fail to destabilize mRNAs of the inflammatory response in macrophages from TTP Ϫ/Ϫ mice (8, 12). Thus, it appears that in these cells, at least, TTP is entirely responsible for the effects on mRNA stability mediated by the p38 MAPK pathway.In additi...

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“…Functional specificity among deadenylases could arise in part through tissue-, cell type- and developmental stage-specific expression as has been observed for the CCR4-NOT (CNOT) complex nuclease subunits CNOT6 and CNOT6L, which form mutually exclusive heterodimer complexes with CNOT7 and CNOT8, and have distinct roles even when co-expressed [23,26,31–34]. Additional functional specialization among deadenylases is likely mediated by divergent amino acid motifs within each protein, even among those sharing catalytic domain structure.…”

Section: Post-transcriptional Control Of Mrna Abundance and Stabilitymentioning

confidence: 99%

“…Biochemical evidence from Drosophila and mammalian cell culture experiments using overexpressed, tagged proteins suggests that components of the CNOT deadenylase complex associate with NOCT [31,35,92]. Like NOCT knockout mice, CNOT3 +/- and CNOT7 -/- mice resist high-fat diet-induced obesity [33,93]; however, it is difficult to assess the extent of phenotypic similarity among these mice as they have not been directly compared under common conditions.…”

Section: Do Noct Protein Partners Control Its Function?mentioning

confidence: 99%

Regulatory roles of vertebrate Nocturnin: insights and remaining mysteries

2018

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Post-transcriptional control of messenger RNA (mRNA) is an important layer of gene regulation that modulates mRNA decay, translation, and localization. Eukaryotic mRNA decay begins with the catalytic removal of the 3′ poly-adenosine tail by deadenylase enzymes. Multiple deadenylases have been identified in vertebrates and are known to have distinct biological roles; among these proteins is Nocturnin, which has been linked to circadian biology, adipogenesis, osteogenesis, and obesity. Multiple studies have investigated Nocturnin’s involvement in these processes; however, a full understanding of its molecular function remains elusive. Recent studies have provided new insights by identifying putative Nocturnin-regulated mRNAs in mice and by determining the structure and regulatory activities of human Nocturnin. This review seeks to integrate these new discoveries into our understanding of Nocturnin’s regulatory functions and highlight the important remaining unanswered questions surrounding its regulation, biochemical activities, protein partners, and target mRNAs.

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Human Ccr4–Not complexes contain variable deadenylase subunits

Cited by 174 publications

References 42 publications

The SMG5–SMG7 heterodimer directly recruits the CCR4–NOT deadenylase complex to mRNAs containing nonsense codons via interaction with POP2

The SMG5–SMG7 heterodimer directly recruits the CCR4–NOT deadenylase complex to mRNAs containing nonsense codons via interaction with POP2

MAPKAP Kinase 2 Blocks Tristetraprolin-directed mRNA Decay by Inhibiting CAF1 Deadenylase Recruitment

Regulatory roles of vertebrate Nocturnin: insights and remaining mysteries

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