RAPAMYCIN INDUCES THE G(0) PROGRAM OF TRANSCRIPTIONAL REPRESSION IN YEAST BY INTERFERING WITH THE TOR SIGNALING PATHWAY

The macrolide antibiotic rapamycin inhibits cellular proliferation by interfering with the highly conserved TOR (for target of rapamycin) si gnaling pathway. Growth arrest of budding yeast cells treated with rap amycin is followed by the program of molecular events that characteriz es entry into G(0) (stationary phase), including the induction of poly merase (Pol) II genes typically expressed only in G(0). Normally, prog ression into G(0) is characterized by transcriptional repression of th e Pol I and III genes. Here, we show that rapamycin treatment also cau ses the transcriptional repression of Pol I and III genes. The down-re gulation of Pol III transcription is TOR dependent. While it coincides ,vith translational repression by rapamycin, transcriptional repressio n is due in part to a translation-independent effect that is evident i n extracts from a conditional tor2 mutant. Biochemical experiments rev eal that RNA Pol III and probably transcription initiation factor TFII IB are targets of repression by rapamycin. In view of previous evidenc e that TFIIIB and Pol III are inhibited when protein phosphatase 2A (P P2A) function is impaired, and that PP2A is a component of the TOR pat hway, our results suggest that TOR signaling regulates Pol I and Pol I II transcription in response to nutrient growth signals.