Translation regulation plays a vital role in the lives of most organisms. It provides an important checkpoint in the pathways for cell growth and differentiation, and a link to the pathology of several diseases. A prominent example of translational regulation in early fly embryogenesis is the repression of maternal hunchback mRNA by Pumilio, Nanos, and Brain tumor. The Nanos protein is only synthesized at the posterior of the embryo due to the translational repression of its own maternal mRNA by Smaug. Pumilio and Nanos are also required for the translation repression of maternal Cyclin B mRNA. Our long-term objective is to uncover the structure and mechanism of assembly of these translational regulators.
Specific aims are: 1. Test our basic hypothesis that two Pumilio molecules bind to a single hunchback regulatory element. This will accomplished through a combination of structure and genetics. 2. Identify specific residues in Brain tumor that interact with Nanos. 3. Cocrystallize Pumilio and Nanos in a ternary complex with hunchback mRNA. 4. Determine the structure of Pumilio Puf domain bound to Cyc B mRNA. We will first define the minimal element in the Cyclin B mRNA that binds Pumilio with high affinity and confers regulation in vivo. 5. Elucidate the structure of a SAM domain/RNA complex by NMR methods. 6. Guided by structure, isolate a Smaug dominant negative for the identification of potential corepressors. Together, these structural and genetic experiments will provide a molecular basis for the translation regulatory events that organize the body pattern along the anterior-posterior axis.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM062947-06
Application #
7046145
Study Section
Special Emphasis Panel (ZRG1-BPC-B (02))
Program Officer
Flicker, Paula F
Project Start
2001-05-01
Project End
2009-04-30
Budget Start
2006-05-01
Budget End
2007-04-30
Support Year
6
Fiscal Year
2006
Total Cost
$333,678
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Physiology
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
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Kadyrova, Lyudmila Y; Habara, Yasuaki; Lee, Tammy H et al. (2007) Translational control of maternal Cyclin B mRNA by Nanos in the Drosophila germline. Development 134:1519-27
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