The synthesis of rRNAs and tRNAs is intimately linked with cell division through the function of tumor suppressors (e.g. p53 and Rb) and oncogenes (e.g. c-myc). The transforming forms of these proteins directly target and up-regulate transcription by RNA polymerases (pols) I and III along with the expression of important cell cycle regulators. The Maf1 protein is a unique regulator of transcription whose properties in human cells are similar to p53 and Rb. Human Maf1 is a candidate tumor suppressor that negatively regulates transcription by all three nuclear RNA polymerases. How Maf1 achieves its effects on transcription is not understood and is complicated by the fact that the protein does not contain any motifs of known function. In S. cerevisiae, Maf1 is essential for repressing transcription by RNA polymerase III and functions to integrate the responses from multiple nutritional and stress signaling pathways that coordinately regulate ribosome and tRNA synthesis. These pathways, like Maf1 itself, are not well defined. The universal requirement for Maf1 in pol III transcriptional repression in yeast provides an extraordinarily valuable model for understanding the pathways and mechanisms regulating ribosome and tRNA synthesis and the biochemical function of this novel signal integrator. Accordingly, the long-term goal of this research is to understand Maf1 structure/function relationships, its interactions with regulatory targets and its interactions with upstream signaling molecules that operate via posttranslational mechanisms to affect Maf1-dependent transcriptional repression.
These aims will be achieved through biochemical studies in well-defined in vitro systems and through the application of an innovative method for phosphopeptide identification. In addition, powerful genome-wide and systematic genetic and biochemical approaches will be used to identify protein kinases and other molecules involved in signaling repression by Maf1. Finally, our understanding of the function and regulation of Maf1 will be advanced by the determination its three-dimensional structure.

Public Health Relevance

Maf1 is a potential tumor suppressor that negatively regulates transcription by all three nuclear RNA polymerase in mammalian cells. In yeast, Maf1 is an essential mediator of transcriptional repression by RNA polymerase III and integrates the responses from multiple nutritional and stress signaling pathways that coordinately regulate ribosome and tRNA synthesis. Our genetic, biochemical and structural studies on on Maf1 will enhance understanding of fundamental cellular processes that are likely to impact cancer biology.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
3R01GM085177-01A1S1
Application #
7894176
Study Section
Molecular Genetics C Study Section (MGC)
Program Officer
Tompkins, Laurie
Project Start
2009-08-13
Project End
2012-07-31
Budget Start
2009-08-13
Budget End
2012-07-31
Support Year
1
Fiscal Year
2009
Total Cost
$220,357
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Biochemistry
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
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Lee, Jaehoon; Moir, Robyn D; McIntosh, Kerri B et al. (2012) TOR signaling regulates ribosome and tRNA synthesis via LAMMER/Clk and GSK-3 family kinases. Mol Cell 45:836-43
Lajoie, Patrick; Moir, Robyn D; Willis, Ian M et al. (2012) Kar2p availability defines distinct forms of endoplasmic reticulum stress in living cells. Mol Biol Cell 23:955-64
Short, Mary K; Hallett, Joshua P; Tar, Krisztina et al. (2012) The yeast magmas ortholog pam16 has an essential function in fermentative growth that involves sphingolipid metabolism. PLoS One 7:e39428

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