: This proposal represents a competitive renewal for a close collaborative effort between two research groups, one with expertise in HIV-1 biology (Chen) and the other with expertise in structural studies of macromolecules (Feigon). HHR23A and its homolog HHR23B were first identified as components of the DNA damage repair nucleotide excision repair (NER) complex. Their function is as yet unclear but within the last two years they have been shown to bind a number of proteins involved in DNA repair and proteasome degradation through at least 3 distinct domains. Considerable new insight has emerged from our studies and other groups on a central role for HHR23A/B in linking cellular processes of DNA repair and ubiquitin/proteasome degradation. HIV-1 Vpr is a protein that has multiple functions, including the ability to arrest cells in the G2/M phase of the cell cycle and to induce apoptosis. The mechanism of the cell cycle arrest and apoptosis remains unclear. We proposed the hypothesis in 1995 that cell cycle arrest was initiated through cellular signaling pathways involving response to DNA damage and apoptosis a consequence of prolonged cell cycle arrest. In support of that hypothesis, we identified HHR23A as a Vpr-binding protein. Failure to repair DNA initiates cell cycle arrest and the ubiquitin-dependent degradation of cell cycle inhibitors may be critical for cell cycle progression. Thus, we believe that Vpr/HHR23A/B interaction is a key step in Vpr mediated cell cycle arrest. The overall objective of the proposed studies is to develop a comprehensive understanding of the structure/function relationships of HHR23A/B in cellular function, particularly as it relates to DNA repair, cell cycle, and ubiquitin/proteasome degradation pathways. This understanding will, in turn, provide us with critical information needed to understand the role of Vpr/HHR23A interaction and to develop potential AIDS therapeutic agents based upon the interaction between these proteins.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI043190-06
Application #
6637802
Study Section
AIDS and Related Research 8 (AARR)
Program Officer
Sharma, Opendra K
Project Start
1998-04-01
Project End
2006-05-31
Budget Start
2003-06-01
Budget End
2004-05-31
Support Year
6
Fiscal Year
2003
Total Cost
$437,395
Indirect Cost
Name
University of California Los Angeles
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Poon, Betty; Chang, Michael A; Chen, Irvin S Y (2007) Vpr is required for efficient Nef expression from unintegrated human immunodeficiency virus type 1 DNA. J Virol 81:10515-23
Mueller, Thomas D; Kamionka, Mariusz; Feigon, Juli (2004) Specificity of the interaction between ubiquitin-associated domains and ubiquitin. J Biol Chem 279:11926-36
Kamionka, Mariusz; Feigon, Juli (2004) Structure of the XPC binding domain of hHR23A reveals hydrophobic patches for protein interaction. Protein Sci 13:2370-7
Mueller, Thomas D; Feigon, Juli (2003) Structural determinants for the binding of ubiquitin-like domains to the proteasome. EMBO J 22:4634-45
Poon, Betty; Chen, Irvin S Y (2003) Human immunodeficiency virus type 1 (HIV-1) Vpr enhances expression from unintegrated HIV-1 DNA. J Virol 77:3962-72
Yuan, Huidong; Xie, Yi-Ming; Chen, Irvin S Y (2003) Depletion of Wee-1 kinase is necessary for both human immunodeficiency virus type 1 Vpr- and gamma irradiation-induced apoptosis. J Virol 77:2063-70
Mueller, Thomas D; Feigon, Juli (2002) Solution structures of UBA domains reveal a conserved hydrophobic surface for protein-protein interactions. J Mol Biol 319:1243-55
Gaynor, E M; Chen, I S (2001) Analysis of apoptosis induced by HIV-1 Vpr and examination of the possible role of the hHR23A protein. Exp Cell Res 267:243-57
Withers-Ward, E S; Mueller, T D; Chen, I S et al. (2000) Biochemical and structural analysis of the interaction between the UBA(2) domain of the DNA repair protein HHR23A and HIV-1 Vpr. Biochemistry 39:14103-12
Stewart, S A; Poon, B; Song, J Y et al. (2000) Human immunodeficiency virus type 1 vpr induces apoptosis through caspase activation. J Virol 74:3105-11