Ccr4-Not Regulates RNA Polymerase I Transcription and Couples Nutrient Signaling to the Control of Ribosomal RNA Biogenesis

Laribee, R. Nicholas; Hosni-Ahmed, Amira; Workman, Jason J.; Chen, Hongfeng

doi:10.1371/journal.pgen.1005113

Cited by 38 publications

(50 citation statements)

References 64 publications

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“…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. Recent reports using in vitro methods have helped to clarify some functional roles of CNOT components (Laribee et al ., 2015; Okada et al ., 2015; Rodriguez‐Gil et al ., 2016). Mice in which CNOT6 has been deleted are viable but, with exception of some bone abnormalities, do not have obvious changes in phenotype.…”

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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“…In yeast cells, deletion of the CCR4 gene resulted in enhanced occupancy of the rDNA by Pol I and CF, increased abundance of pre-rRNA species, and increased abundance of the Pol I transcription factor Rrn3 [158]. Together, all of these observations provide support for a role for Ccr4-Not in transcription initiation by Pol I.…”

Section: Ccr4-notmentioning

confidence: 99%

“…Although the direct or indirect mechanism by which this effect is induced is unclear, given the many roles of Ccr4-Not in gene expression, it is clear that Ccr4 has a repressive effect on transcription by Pol I under the conditions tested. This repressive effect is likely mediated at least partially through interactions with Rrn3 because deletion of CCR4 causes enhanced Rrn3 expression and initiation-competent Rrn3-Pol I complexes [158]. …”

Section: Ccr4-notmentioning

confidence: 99%

“…A12 is a paralogue of TFIIS and is thought to influence transcription elongation and termination [158, 159]. They found that Pol I occupancy of the rDNA and rRNA synthesis are decreased in double mutant of ccr4 Δ rpa12 Δ compared to either single mutant or WT.…”

Section: Ccr4-notmentioning

confidence: 99%

“…Furthermore, in the presence of 6-AU in rich medium in the ccr4 Δ rpa12 Δ cells, Pol I remains on rDNA. This observation led to the conclusion that the absence of Ccr4-Not caused slowed transcription elongation by Pol I [158]. More investigation is required to identify a potential mechanism by which this effect could be mediated.…”

Section: Ccr4-notmentioning

confidence: 99%

See 2 more Smart Citations

Transcription factors that influence RNA polymerases I and II: To what extent is mechanism of action conserved?

Zhang

Najmi

Schneider

2017

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

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In eukaryotic cells, nuclear RNA synthesis is accomplished by at least three unique, multisubunit RNA polymerases. The roles of these enzymes are generally partitioned into the synthesis of the three major classes of RNA: rRNA, mRNA, and tRNA for RNA polymerases I, II, and III respectively. Consistent with their unique cellular roles, each enzyme has a complement of specialized transcription factors and enzymatic properties. However, not all transcription factors have evolved to affect only one eukaryotic RNA polymerase. In fact, many factors have been shown to influence the activities of multiple nuclear RNA polymerases. This review focuses on a subset of these factors, specifically addressing the mechanisms by which these proteins influence RNA polymerases I and II.

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The RNA polymerase I subunit Rpa12p interacts with the stress‐responsive transcription factor Msn4p to regulate lipid metabolism in budding yeast

et al. 2016

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In Saccharomyces cerevisiae, RPA12 encodes the small subunit of RNA polymerase I. Here, we demonstrate that Rpa12p interacts with the transcription factor Msn4p and prevents its binding to the promoter of AYR1 encoding Ayr1p (1-acyldihydroxyacetone phosphate reductase), a key enzyme involved in triacylglycerol biosynthesis and mobilization of nonpolar lipids. Deletion of RPA12 leads to triacylglycerol accumulation due to the binding of Msn4p to the promoter of AYR1 and activation of its transcription. The double deletion rpa12Δ::ayr1Δ caused a reduction in triacylglycerol levels. Our findings reveal that Rpa12p functions as a negative regulator of lipid metabolism by modulating nonpolar lipid biosynthesis through its interaction with Msn4p.

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Ccr4-Not Regulates RNA Polymerase I Transcription and Couples Nutrient Signaling to the Control of Ribosomal RNA Biogenesis

Cited by 38 publications

References 64 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

Transcription factors that influence RNA polymerases I and II: To what extent is mechanism of action conserved?

The RNA polymerase I subunit Rpa12p interacts with the stress‐responsive transcription factor Msn4p to regulate lipid metabolism in budding yeast

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