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Research Interests
Reproductive Toxicology and Pregnancy
Research Summary
The long-term goal of our work is to understand the mechanism
behind the development of morbidity and mortality in infants
congenitally infected with human cytomegalovirus (HCMV). In the
last 5 years we have shown that HCMV interacts with the key cell
cycle regulatory protein p53 and sequesters it from its normal
cellular partners (Fortunato and Spector 1998),
thereby disabling its capacity to control cell cycle arrest and
apoptosis in the infected cell. This sequestration into the viral
replication centers is not unique for p53, but also occurs for
several proteins of the DNA repair machinery. We have also recently
shown that specific breaks are induced on chromosome 1q in the
permissive host cell when infection is initiated during S-phase
(Fortunato, Dell'Aquila and Spector 2000).
This damage does not require de novo viral protein
expression, which has tremendous implications for infection of
semi- to non-permissive cell types like those in the developing
fetal brain. Our results, when coupled with the existing
literature, highlight the genotoxic effects of HCMV. Our objective
is to study the importance of both the timing of infection and the
permissivity of the host cell on the interaction of HCMV with the
host cell's DNA and DNA repair machinery. In this way, we wish
to delineate the role of this infectious agent in adverse outcomes
during pregnancy.
Two main projects are progressing in the lab at this time. The
first deals with the interaction of HCMV with the key cell cycle
regulatory protein p53. We are interested in the initial
upregulation of the protein by viral infection. We wish to
determine the mechanism of stabilization of the protein and of its
sequestration into the viral replication centers once they are
formed. In addition, we wish to determine the role (if any) of the
p53 in maintaining the fidelity of viral replication and repair.
The second main project is studying the ability of virus-infected
cells to repair insult to the cellular DNA (either virus or
externally imposed). Can a cell that is damaged specifically at the
chromosome 1 sites repair that damage? If not, does the damage get
passed on to subsequent daughter populations? Also, once viral
replication centers are set up within the virus-infected nucleus,
is there a preferential repair of viral over cellular DNA due to
sequestration of the cellular components of the DNA repair
machinery into the viral replication centers? It is our goal to
ascertain whether these genotoxic interactions lead to the defects
in the sensorineural system observed in congenitally infected
infants. (The work in my lab is currently funded by NIH.)
Research Publications
Jault, F.M., J-M. Jault, F. Ruchti, E.A. Fortunato, C. Clark, J. Corbeil, D.D. Richman, and D.H. Spector. 1995. Cytomegalovirus infection induces high levels of cyclins, phosphorylated Rb, and p53, leading to cell cycle arrest. J.Virol. 69:6697-6704.
E.A. Fortunato, M.H. Sommer, K. Yoder and D.H. Spector. 1997. Identification of domains within the Human Cytomegalovirus IE2 86 protein and the Retinoblastoma protein required for physical and functional interactions with each other. J. Virol. 71:8176-8185.
E.A. Fortunato and D.H. Spector. 1998. p53 and RPA are sequestered in viral replication centers in the nucleus of cells infected with Human Cytomegalovirus. J. Virol. 72:2033-2039.
B.S. Salvant, E.A. Fortunato, and D.H Spector. 1998. Cell cycle dysregulation by Human Cytomegalovirus: Influence of the cell cycle phase at the time of infection and effects on cyclin transcription. J. Virol. 72:3729-3741.
Fortunato, E.A. and D.H. Spector. 1999. Regulation of human cytomegalovirus gene expression. Adv. Virus Res. Vol. 54: 61-128.
Fortunato, E. A., M. L. Dell'Aquila and D. H. Spector. 2000. Specific chromosome 1 breaks induced by human cytomegalovirus. Proc. Natl. Acad. Sci. USA 97(2): 853-858.
Fortunato, E.A., A.K. McElroy, V. Sanchez and D.H. Spector. 2000. Exploitation of cellular signaling and regulatory pathways by human cytomegalovirus. Trends in Microbio. 8(3): 111-119.
Fortunato, E.A., V. Sanchez, J.Y. Yen and D.H. Spector. 2002. Infection of cells with human cytomegalovirus during S-phase results in a blockade to immediate early gene expression that can be overcome by inhibition of the proteasome. J. Virol. 76(11): 5369-5379.
Fortunato, E.A. and D.H. Spector. 2003. Viral
induction of site-specific chromosome damage. Rev. in Med. Virol.
13: 21-37.
Rosenke, K. and E.A. Fortunato 2004. Bromodeoxyuridine-labeled
viral particles as a tool for visualization of the immediate-early
events of human cytomegalovirus infection. J Virol. 78:
7818-22.
Rosenke, K. and E.A. Fortunato 2004. Bromodeoxyuridine-labeled viral particles as a tool for visualization of the immediate-early events of human cytomegalovirus infection. J Virol. 78: 7818-22.
N. C. Casavant, M. Luo, K. Rosenke, T. Winegardner, A. Zurawska and E.A. Fortunato. 2006 A Potential Role for p53 in the Permissive Life Cycle of Human Cytomegalovirus J. Virology 2006 Sep;80(17):8390-401.
K. Rosenke, M. A. Samuel, E. T. McDowell, M. A. Toerne and
E. A. Fortunato. 2006 An intact sequence-specific
DNA binding domain is required for human cytomegalovirus-mediated
sequestration of p53 and may promote in vivo binding to the viral
genome during infection. Virology 348(1): 19-34.