Rapamycin induces the G0 program of transcriptional repression in yeast by interfering with the TOR signaling pathway
D Zaragoza1, A Ghavidel, J Heitman
1Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada T6G 2H7.
Abstract:
The macrolide antibiotic rapamycin inhibits cellular proliferation by interfering with the highly conserved TOR (for target of rapamycin) signaling pathway. Growth arrest of budding yeast cells treated with rapamycin is followed by the program of molecular events that characterizes entry into G0 (stationary phase), including the induction of polymerase (Pol) II genes typically expressed only in G0. Normally, progression into G0 is characterized by transcriptional repression of the Pol I and III genes. Here, we show that rapamycin treatment also causes the transcriptional repression of Pol I and III genes. The down-regulation of Pol III transcription is TOR dependent. While it coincides with translational repression by rapamycin, transcriptional repression is due in part to a translation-independent effect that is evident in extracts from a conditional tor2 mutant. Biochemical experiments reveal that RNA Pol III and probably transcription initiation factor TFIIIB are targets of repression by rapamycin. In view of previous evidence that TFIIIB and Pol III are inhibited when protein phosphatase 2A (PP2A) function is impaired, and that PP2A is a component of the TOR pathway, our results suggest that TOR signaling regulates Pol I and Pol III transcription in response to nutrient growth signals.
Insights
Rapamycin, an antibiotic, halts cell growth by impacting the TOR pathway. It also represses RNA Polymerase I and III (Pol I and Pol III) transcription, revealing a new role for TOR signaling in nutrient response.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Rapamycin inhibits cellular proliferation by targeting the conserved Target of Rapamycin (TOR) signaling pathway.
- TOR pathway regulates cell growth and metabolism in response to nutrient availability.
- Yeast cells treated with rapamycin enter G0 (stationary phase), involving gene expression changes.
Purpose of the Study:
- To investigate the effect of rapamycin on RNA Polymerase I and III (Pol I and Pol III) gene transcription.
- To determine if the repression of Pol I and Pol III transcription by rapamycin is dependent on the TOR pathway.
- To identify the molecular targets of rapamycin-mediated repression of Pol I and Pol III transcription.
Main Methods:
- Treatment of budding yeast cells with rapamycin.
- Analysis of gene expression for Pol I, II, and III genes.
- Biochemical assays using cell extracts, including from a conditional tor2 mutant.
- Investigation of RNA Pol III and transcription initiation factor TFIIIB activity.
Main Results:
- Rapamycin treatment leads to transcriptional repression of Pol I and Pol III genes.
- The down-regulation of Pol III transcription is dependent on the TOR pathway.
- Transcriptional repression of Pol III is partially translation-independent.
- RNA Pol III and TFIIIB are identified as targets of rapamycin-mediated repression.
Conclusions:
- TOR signaling regulates both Pol I and Pol III transcription in response to nutrient growth signals.
- This regulation involves direct or indirect inhibition of RNA Pol III and TFIIIB.
- The findings link TOR pathway activity to the control of essential transcription machinery.
Related Concept Videos
Negative Regulator Molecules
Eukaryotic Transcription Inhibitors
Eukaryotic transcription inhibitors usually contain two distinct domains, a DNA...
mTOR Signaling and Cancer Progression
The mTOR pathway or the...
PI3K/mTOR/AKT Signaling Pathway
Repressible Operon: trp Operon
Transcriptional Regulation: Riboswitches


