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Regulation of RNA Polymerase III-dependent transcription by TORC1 and Ypt1 modulation of TORC1 at the Golgi apparatus to sense environmental nutrients

by
Yuehua Wei
M.S. Chinese Academy of Sciences - 2002

Thesis Advisor: X.F. Steven Zheng, Ph.D.
Graduate Program in Cellular & Molecular Pharmacology

RWJMS Research Tower
5th floor Conference Room
Piscataway

Wednesday, September 22, 2010
12:00 noon


Abstract

RNA polymerase III (Pol III) synthesizes 5S ribosomal RNA (rRNA), tRNAs and other species of small regulatory RNAs. Similar to Pol I, which transcribes 35S rRNA, Pol III is essential for cell growth and highly targeted by oncogenic transformations. Previous studies have found that TORC1 binds to both 35S and 5S rDNA and had demonstrated the importance of 35S association. However, the significance of 5S association and the mechanistic regulation of Pol III by TORC1 at this chromatin site remain unknown. This thesis shows that TORC1 binds to 5S rDNA is essential for Pol III-dependent transcription, and that TORC1 simultaneously binds 35S and 5S rDNA to coordinate Pol I and Pol III. Mechanistically, TORC1 directly phosphorylates Pol III repressor Maf1 at the rDNA chromatin site, preventing Maf1 nucleolar localization and targeting to Pol III-dependent genes. This thesis further shows that Sch9 facilitates TORC1 regulation of Pol III by phosphorylation and cytoplamic retention of Maf1, but is dispensable for TORC1 to control Pol III and cell growth. Altogether, these studies provide new mechanistic insights into the regulation of ribosome biogenesis by TORC1 at the chromatin level.

TORC1 encodes signals for the environmental nutrients and relays to downstream effectors to control cell growth. How and where such nutrient sensing machineries execute in the cell is not well studied. Recent studies suggest the involvement of small GTPase along the secretory pathway. We therefore screen all the Rab GTPases through genomic chemical assay and identify Ypt1 as a modulator of TORC1. Further characterization reveals that Ypt1 is essential for nutrient sensing by TORC1. Mechanistically, Ypt1 association with TORC1 at the Golgi apparatus is required for TORC1 activation. Starvation delocalizes TORC1 from Golgi and dissociates TORC1-Ypt1 association. Therefore, we have found a TORC1 regulator that modulates environmental nutrient sensing at the Golgi apparatus.


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