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.
Highlights
Eukaryotic cells alter gene expression programs in response to changes in their environment, including nutrient availability and the presence of stress, by transmitting this information through nutrient-responsive signaling cascades to the transcriptional machinery [1]
All cells communicate their environmental nutrient status to the gene expression machinery so that transcription occurs in proportion to the nutrients available to support cell growth and proliferation. mechanistic target of rapamycin complex 1 (mTORC1) signaling, which is essential for this process, regulates
We provide evidence that the RNA polymerase II regulatory complex, Ccr4-Not, is a novel Pol I regulator required for mTORC1-dependent control of Pol I activity
Summary
Eukaryotic cells alter gene expression programs in response to changes in their environment, including nutrient availability and the presence of stress, by transmitting this information through nutrient-responsive signaling cascades to the transcriptional machinery [1]. This process is critically important for regulating rDNA transcription and ribosomal RNA (rRNA) biogenesis. Coordinating ribosomal transcription by these three distinct polymerases to produce ribosomal components in the appropriate stochiometries, and in proportion to nutrient availability, is critical Dysregulation of this process may result in the formation of partial or non-functional ribosomes that could have deleterious effects on cell fitness. Promoting ribosomal biogenesis in nutrient poor environments may suppress the ability of cells to enter into survival states, such as autophagy, which could reduce viability [3]
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