The focus of the work proposed here is the La autoantigen, a protein that associates with all known polymerase III transcripts immediately after their synthesis. First described as a target of the autoimmune response in patients with systemic lupus erythematosus and Sjogren's syndrome, this nuclear phosphoprotein appears to be a component of all eukaryotic cells. Although S. cerevisiae cells lacking the La protein are viable, the applicant has identified several genes that, when mutated, cause the La protein to become essential for growth. Analysis of one of these mutations has revealed that the yeast La protein is required for the 3' endonucleolytic cleavage of many tRNA precursors. In the absence of the La protein, the 3' end of these pre-tRNAs is trimmed by exonuclease(s).
The first aim of the proposal is to extend the molecular characterization of the role of the La protein in the 3' processing of the polymerase III transcripts.
The second aim i s to characterize the mutations in four other complementation groups that cause yeast cells to require the La protein.
The third aim i s to use immunoprecipitation and affinity chromatography to identify proteins that interact with the yeast La protein.
The fourth aim i s to determine the functions of two yeast proteins that share a highly conserved domain with all known La proteins. The proposed studies will extend our knowledge of the biogenesis of polymerase III transcripts, including transcription, processing, folding, assembly into RNPs, and intracellular sorting. They may also provide clues as to why the La protein is a target of the immune response in certain autoimmune diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM048410-09
Application #
6363257
Study Section
Molecular Cytology Study Section (CTY)
Program Officer
Rhoades, Marcus M
Project Start
1993-01-01
Project End
2002-02-28
Budget Start
2001-03-01
Budget End
2002-02-28
Support Year
9
Fiscal Year
2001
Total Cost
$137,692
Indirect Cost
Name
Yale University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
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