The tumor suppressor protein p53 plays an essential role in the suppression of malignant cancer. The cellular protein HAUSP was recently identified to be a p53-specific deubiquitinating protease and plays an important role in the stabilization of p53 in vivo. HAUSP also represents the first member of the UBP (ubiquitin-specific protease) family of deubiquitinases with a specific physiologic substrate. To elucidate the mechanisms of p53-specific deubiquitination, the following specific aims are proposed: (1) Determination of the structures of the catalytic core domain of HAUSP by itself and in complex with ubiquitin aldehyde. Comparison of the structure of HAUSP by itself with that of HAUSP bound to ubiquitin aldehyde will reveal important mechanistic information on the UBP family of deubiquitinases. (2) Determination of the structure of a recognition complex involving the N-terminal domain of HAUSP and p53. Structure of this complex will reveal the mechanism of specific p53 recognition by HAUSP. (3) Determination of the structures of a functional HAUSP-p53 complex in the presence and absence of ubiquitin aldehyde. These structures will reveal the mechanisms of HAUSP-mediated p53 deubiquitination. In particular, these structures will reveal how the recognition of p53 is coupled to its deubiquitination. (4) Determination of the structures of the full-length HAUSP by itself and bound to p53. This study will reveal the regulation of HAUSP-mediated p53 deubiquitination.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA100359-03
Application #
6875046
Study Section
Biophysical Chemistry Study Section (BBCB)
Program Officer
Knowlton, John R
Project Start
2003-04-01
Project End
2008-03-30
Budget Start
2005-04-01
Budget End
2006-03-31
Support Year
3
Fiscal Year
2005
Total Cost
$281,240
Indirect Cost
Name
Princeton University
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
002484665
City
Princeton
State
NJ
Country
United States
Zip Code
08544