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

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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. mTORC1 signaling, which is essential for this process, regulates Pol I-dependent rRNA expression. We provide evidence that the RNA polymerase II regulatory complex, Ccr4-Not, also is a novel Pol I regulator required for mTORC1-dependent control of Pol I activity. Ccr4-Not disruption increases Pol I transcription due to an inability to decrease Pol I interactions with the transcription factor Rrn3 when mTORC1 signaling is reduced. Additionally, genetic and biochemical evidence supports a role for Ccr4-Not as a positive regulator of Pol I transcription elongation as well. Surprisingly, while Ccr4-Not mutations profoundly inhibit growth when mTORC1 activity is reduced, this phenotype is reversed by simultaneously impairing Pol I transcription. Overall, our data demonstrate that the evolutionarily conserved Ccr4-Not complex mediates environmental signaling through mTORC1 to control Pol I transcription initiation and, additionally, to regulate Pol I elongation. These studies further suggest that uncoupling Pol I from upstream mTORC1 activity by targeting Ccr4-Not sensitizes cells to mTORC1 inhibitors which is a concept that could have implications for anti-cancer drug development.

Vyšlo v časopise: Ccr4-Not Regulates RNA Polymerase I Transcription and Couples Nutrient Signaling to the Control of Ribosomal RNA Biogenesis. PLoS Genet 11(3): e32767. doi:10.1371/journal.pgen.1005113
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005113

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