description): This proposal uses a combination of biochemical and x-ray crystallographic approaches to study the structural basis of aberrant RNA processing in genetic disease. CUG-binding protein (CUG-BP), ELAV-type RNA-binding protein (ETR) -1 and -3 are proteins responsible for developmentally regulated splice site selection in a variety of tissues and cell types. These proteins contain 3 copies of the RNA recognition motif (RRM) and participate in a wide range of RNA processing events including, splicing, transport and mRNA turnover. CUG-BP, ETR-1 and ETR-3 specifically effect splice site selection in striated muscle tissue. CUG-BP was first isolated in connection with myotonic dystrophy (DM), a genetic disease that results from an expansion of CUG repeats in an untranslated region of the myotonin kinase gene and results in symptoms from mild myotonia to severe retardation at birth. DM is an unfortunately common disease (1 in 8000 births). CUG-BP also interacts with CUG-rich sequences found in a number of other mRNAs. Alteration of in vivo levels of CUG-BP, ETR- 1 or ETR-3 result in tissue specific changes in splicing that appear to mimic either developmental or disease related RNA processing defects. This award would be used to examine how RNA sequences already involved in ribonucleoprotein complexes are read or """"""""scanned"""""""" by other RNA binding proteins such as those involved in alternate splicing. Crystallographic conditions required to determine the three-dimensional structure of CUG-BP, ETR-1, and ETR-3 bound to their physiologically relevant RNA targets using x- ray crystallography will also be determined. The results derived from this proposal will significantly broaden our understanding of how aberrant RNA splicing occurs and address fundamental aspects of RNA metabolism to provide immediate insights to investigators working in the field of human disease pathogenesis.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Small Research Grants (R03)
Project #
5R03HD039658-02
Application #
6536230
Study Section
Pediatrics Subcommittee (CHHD)
Program Officer
Javois, Lorette Claire
Project Start
2001-04-01
Project End
2004-03-31
Budget Start
2002-04-01
Budget End
2004-03-31
Support Year
2
Fiscal Year
2002
Total Cost
$74,500
Indirect Cost
Name
Rice University
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
050299031
City
Houston
State
TX
Country
United States
Zip Code
77005
Shamoo, Yousif (2003) Structural insights into BRCA2 function. Curr Opin Struct Biol 13:206-11