Novel roles of the multi-functional CCR4-NOT complex in post-transcriptional regulation

Inada, Toshifumi; Makino, Shiho

doi:10.3389/fgene.2014.00135

Cited by 46 publications

(38 citation statements)

References 88 publications

(128 reference statements)

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“…The CCR4‐NOT complex is a key regulator of mRNA stability, microRNA function, and preferential translation, and functions as a check point in the control of translation and protein degradation (Inada & Makino, 2014; Shirai et al ., 2014). The CCR4‐NOT complex is comprised of at least ten subunits, but there is limited information about the function of individual components of the complex in mammals.…”

Section: Introductionmentioning

confidence: 99%

mTOR regulates the expression of DNA damage response enzymes in long‐lived Snell dwarf, GHRKO, and PAPPA‐KO mice

Dominick

Bowman

et al. 2016

Aging Cell

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SummaryStudies of the mTOR pathway have prompted speculation that diminished mTOR complex‐1 (mTORC1) function may be involved in controlling the aging process. Our previous studies have shown diminished mTORC1 activity in tissues of three long‐lived mutant mice: Snell dwarf mice, growth hormone receptor gene disrupted mice (GHRKO), and in this article, mice deficient in the pregnancy‐associated protein‐A (PAPPA‐KO). The ways in which lower mTOR signals slow aging and age‐related diseases are, however, not well characterized. Here, we show that Snell, GHKRO, and PAPPA‐KO mice express high levels of two proteins involved in DNA repair, O‐6‐methylguanine‐DNA methyltransferase (MGMT) and N‐myc downstream‐regulated gene 1 (NDRG1). Furthermore, we report that lowering mTOR enhances MGMT and NDRG1 protein expression via post‐transcriptional mechanisms. We show that the CCR4‐NOT complex, a post‐transcriptional regulator of gene expression, is downstream of the mTORC1 pathway and may be responsible for the upregulation of MGMT and NDRG1 in all three varieties of long‐lived mice. Our data thus suggest a novel link between DNA repair and mTOR signaling via post‐transcriptional regulation involving specific alteration in the CCR4‐NOT complex, whose modulation could control multiple aspects of the aging process.

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Section: Introductionmentioning

confidence: 99%

mTOR regulates the expression of DNA damage response enzymes in long‐lived Snell dwarf, GHRKO, and PAPPA‐KO mice

Dominick

Bowman

et al. 2016

Aging Cell

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“…AU-rich element (ARE) binding proteins, such as tristetraprolin (TTP) and its homologs, also bind directly to NOT1 to initiate deadenylation via the associated CAF1 (Sandler et al 2011;Fabian et al 2013). The CCR4-NOT complex is thus recruited to mRNAs by miRNAs and RNA-binding proteins (RBPs) to elicit translational repression or decay of the transcript (Braun et al 2011;Chekulaeva et al 2011;Fabian et al 2011;Sandler et al 2011;Wahle and Winkler 2013;Bhandari et al 2014;Chen et al 2014;Inada and Makino 2014;Mathys et al 2014;Rouya et al 2014;Temme et al 2014).…”

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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“…Ccr4-Not is a conserved complex involved in RNA surveillance, transcription elongation, RNA export, and DNA repair (Collart and Panasenko 2012;Miller and Reese 2012;Wahle and Winkler 2013;Inada and Makino 2014). The Ccr4-Not complex is the primary deadenylase and is essential for downstream decapping and mRNA decay by Xrn1 (Schizosaccharomyces pombe: Exo2), a conserved 5 ′ -3 ′ exoribonuclease (Collart and Panasenko 2012;Miller and Reese 2012).…”

mentioning

confidence: 99%

Accumulation of RNA on chromatin disrupts heterochromatic silencing

Brönner¹,

Salvi²,

Zocco³

et al. 2017

Genome Res.

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Long noncoding RNAs (lncRNAs) play a conserved role in regulating gene expression, chromatin dynamics, and cell differentiation. They serve as a platform for RNA interference (RNAi)-mediated heterochromatin formation or DNA methylation in many eukaryotic organisms. We found in Schizosaccharomyces pombe that heterochromatin is lost at transcribed regions in the absence of RNA degradation. We show that heterochromatic RNAs are retained on chromatin, form DNA: RNA hybrids, and need to be degraded by the Ccr4-Not complex or RNAi to maintain heterochromatic silencing. The Ccr4-Not complex is localized to chromatin independently of H3K9me and degrades chromatin-associated transcripts, which is required for transcriptional silencing. Overexpression of heterochromatic RNA, but not euchromatic RNA, leads to chromatin localization and loss of silencing of a distant ade6 reporter in wild-type cells. Our results demonstrate that chromatin-bound RNAs disrupt heterochromatin organization and need to be degraded in a process of heterochromatin formation.

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Novel roles of the multi-functional CCR4-NOT complex in post-transcriptional regulation

Cited by 46 publications

References 88 publications

mTOR regulates the expression of DNA damage response enzymes in long‐lived Snell dwarf, GHRKO, and PAPPA‐KO mice

mTOR regulates the expression of DNA damage response enzymes in long‐lived Snell dwarf, GHRKO, and PAPPA‐KO mice

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

Accumulation of RNA on chromatin disrupts heterochromatic silencing

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