title: Ccr4-not regulates RNA polymerase I transcription and couples nutrient signaling to the control of ribosomal RNA biogenesis.
abstract: Ribosomal RNA synthesis is controlled by nutrient signaling through the mechanistic target of rapamycin complex 1 (mTORC1) pathway. mTORC1 regulates ribosomal RNA expression by affecting RNA Polymerase I (Pol I)-dependent transcription of the ribosomal DNA (rDNA) but the mechanisms involved remain obscure. This study provides evidence that the Ccr4-Not complex, which regulates RNA Polymerase II (Pol II) transcription, also functions downstream of mTORC1 to control Pol I activity. Ccr4-Not localizes to the rDNA and physically associates with the Pol I holoenzyme while Ccr4-Not disruption perturbs rDNA binding of multiple Pol I transcriptional regulators including core factor, the high mobility group protein Hmo1, and the SSU processome. Under nutrient rich conditions, Ccr4-Not suppresses Pol I initiation by regulating interactions with the essential transcription factor Rrn3. Additionally, Ccr4-Not disruption prevents reduced Pol I transcription when mTORC1 is inhibited suggesting Ccr4-Not bridges mTORC1 signaling with Pol I regulation. Analysis of the non-essential Pol I subunits demonstrated that the A34.5 subunit promotes, while the A12.2 and A14 subunits repress, Ccr4-Not interactions with Pol I. Furthermore, ccr4Δ is synthetically sick when paired with rpa12Δ and the double mutant has enhanced sensitivity to transcription elongation inhibition suggesting that Ccr4-Not functions to promote Pol I elongation. Intriguingly, while low concentrations of mTORC1 inhibitors completely inhibit growth of ccr4Δ, a ccr4Δ rpa12Δ rescues this growth defect suggesting that the sensitivity of Ccr4-Not mutants to mTORC1 inhibition is at least partially due to Pol I deregulation. Collectively, these data demonstrate a novel role for Ccr4-Not in Pol I transcriptional regulation that is required for bridging mTORC1 signaling to ribosomal RNA synthesis.
authors: University of Tennessee Health Science Center Department of Pathology and Laboratory Medicine and the UT Center for Cancer Research, Memphis, Tennessee, United States of America.
authors: R Nicholas
authors: RN
authors: Laribee
authors: University of Tennessee Health Science Center Department of Pathology and Laboratory Medicine and the UT Center for Cancer Research, Memphis, Tennessee, United States of America.
authors: Amira
authors: A
authors: Hosni-Ahmed
authors: University of Tennessee Health Science Center Department of Pathology and Laboratory Medicine and the UT Center for Cancer Research, Memphis, Tennessee, United States of America.
authors: Jason J
authors: JJ
authors: Workman
authors: University of Tennessee Health Science Center Department of Pathology and Laboratory Medicine and the UT Center for Cancer Research, Memphis, Tennessee, United States of America.
authors: Hongfeng
authors: H
authors: Chen
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D015966:Gene Expression Regulation, Fungal; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000235:genetics* / Q000378:metabolism; D035463:Pol1 Transcription Initiation Complex Proteins / Q000235:genetics / Q000378:metabolism; D012318:RNA Polymerase I / Q000096:biosynthesis* / Q000235:genetics; D012319:RNA Polymerase II / Q000096:biosynthesis / Q000235:genetics; D012335:RNA, Ribosomal / Q000096:biosynthesis; D012260:Ribonucleases / Q000235:genetics* / Q000378:metabolism; D012270:Ribosomes / Q000235:genetics; D012441:Saccharomyces cerevisiae; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: C079592:CDC39 protein, S cerevisiae; D018797:Cell Cycle Proteins; D046912:Multiprotein Complexes; D035463:Pol1 Transcription Initiation Complex Proteins; D012335:RNA, Ribosomal; C101161:RRN3 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D012319:RNA Polymerase II; D012318:RNA Polymerase I; C078657:CCR4 protein, S cerevisiae; D012260:Ribonucleases