The Human T-Cell Leukemia Virus type 1 causes Adult T-Cell Leukemia and HTLV-Associated Myelopathy/Tropical Spastic Paraparesis. It is believed that transformation of the infected T-cell by the viral protein Tax results in disease. The process by which Tax mediates cellular transformation is not well understood but is thought to involve Tax-mediated cellular genomic instability. The objective of these studies is to uncover the mechanism by which Tax disrupts normal cellular DNA damage recognition-repair response, thus promoting genomic instability. We specifically hypothesize that Tax targets to and functionally disrupts a nuclear complex that regulates key aspects of cellular DNA damage response, repair recognition and checkpoint activation. We propose (and will confirm) that the nuclear complex targeted by Tax is the same """"""""damage foci"""""""" described in the general literature as forming in response to DNA damage. We will use live-cell deconvolution and confocal microscopy to define the mechanism by which Tax targets this complex. The component make-up and physical characteristics of the Tax-containing complexes will be determined using sophisticated mass spectrometry based approaches. The structural and functional impact of Tax on these complexes will be revealed by a combination of quantitative proteomics and molecular functional assays. The successful completion of the studies described in this proposal will provide a mechanism by which expression of Tax results in genomic instability. Elucidation of this cause and effect model will contribute significantly to our understanding of HTLV-1-mediated disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA076595-11
Application #
7615650
Study Section
Virology - A Study Section (VIRA)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
1999-06-15
Project End
2011-04-30
Budget Start
2009-05-01
Budget End
2011-04-30
Support Year
11
Fiscal Year
2009
Total Cost
$210,269
Indirect Cost
Name
Eastern Virginia Medical School
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
058625146
City
Norfolk
State
VA
Country
United States
Zip Code
23501
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