Human adenoviruses are under intense scrutiny as vehicles for gene therapy and as anticancer agents in humans. Nevertheless, many basic aspects of the mechanisms by which these viruses replicate efficiently in permissive cells remain poorly understood. These processes include the co-ordination of synthesis of progeny viral DNA genome with production of the structural proteins of virus particles. In adenovirus-infected cells, transcription of the genes encoding the latter proteins requires viral DNA synthesis. The long term objective of these studies is elucidation of the mechanisms by which viral and cellular components co-operate in such temporal regulation of viral transcription. To this end, a cellular transcriptional repressor responsible for the viral DNA synthesis-dependent transcription of the late IVa2 gene will be identified and characterized, so that its normal function and mechanism of action can be investigated. The protein encoded by the IVa2 gene is a sequence-specific DNA binding protein that has been implicated in stimulation of transcription from the promoter of the major late transcription, which contains the coding sequences for all but one structural protein, and in virion assembly. Complementary biochemical, molecular and genetic methods will be used to establish the roles of this important viral protein in infected cells and investigate the mechanisms by which it acts. The possibility that a novel mechanism regulates the rate at which the viral replication proteins are produced will also be assessed by genetic methods.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM037705-17
Application #
7210543
Study Section
Special Emphasis Panel (ZRG1-EVR (01))
Program Officer
Tompkins, Laurie
Project Start
1986-12-01
Project End
2009-03-31
Budget Start
2007-04-01
Budget End
2009-03-31
Support Year
17
Fiscal Year
2007
Total Cost
$313,396
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
Pérez-Berná, Ana J; Mangel, Walter F; McGrath, William J et al. (2014) Processing of the l1 52/55k protein by the adenovirus protease: a new substrate and new insights into virion maturation. J Virol 88:1513-24
Ortega-Esteban, A; Pérez-Berná, A J; Menéndez-Conejero, R et al. (2013) Monitoring dynamics of human adenovirus disassembly induced by mechanical fatigue. Sci Rep 3:1434
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Blainey, Paul C; Graziano, Vito; Pérez-Berná, Ana J et al. (2013) Regulation of a viral proteinase by a peptide and DNA in one-dimensional space: IV. viral proteinase slides along DNA to locate and process its substrates. J Biol Chem 288:2092-102
Pérez-Berná, Ana J; Ortega-Esteban, Alvaro; Menéndez-Conejero, Rosa et al. (2012) The role of capsid maturation on adenovirus priming for sequential uncoating. J Biol Chem 287:31582-95
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LeRoy, Gary; Rickards, Brenden; Flint, S J (2008) The double bromodomain proteins Brd2 and Brd3 couple histone acetylation to transcription. Mol Cell 30:51-60
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Chen, H; Flint, S J (1992) Mutational analysis of the adenovirus 2 IVa2 initiator and downstream elements. J Biol Chem 267:25457-65

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