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Thesis Defense Announcement
To:  The George Mason University Community

*Candidate: Alan Baer
Program: Master of Science in Biology
*
*Date:   Tuesday July 26, 2011
Time:   10:00 a.m.
Place:  George Mason University, Prince William campus <http://www.gmu.edu/resources/visitors/findex.html>
	     Bull Run Hall, Room 246
 
*Thesis Chair:  Dr. Kylene Kehn-Hall

Title: " Induction of DNA Damage Signaling Cascade Upon Rift Valley Fever Virus (RVFV) Infection"***
*

A copy of the thesis is on reserve in the Johnson Center Library, 
Fairfax campus.  The thesis will not be read at the meeting, but should 
be read in advance. All members of the George Mason University community 
are invited to attend.

*ABSTRACT:*
Rift Valley fever virus (RVFV), family Bunyaviridae, is a highly 
pathogenic arthropod-borne virus infecting a wide range of vertebrate 
hosts.  Of particular interest is the replication dispensable NSs 
protein, a major virulence factor, which unique among cytoplasmic 
replicating bunyaviruses forms large filamentous fibril bundles in the 
nucleus.  Past studies have shown NSs to be a multifaceted protein, 
inducing the post-transcriptional down regulation of dsRNA-dependent 
protein kinase (PKR), preventing phosphorylation of eIF2alpha and 
promoting viral translation in infected cells, as well as acting as a 
general inhibitor of IFN and cellular transcription.  Our previous 
studies indicated that p53 was phosphorylated at Ser15 and Ser46 as well 
as demonstrating an increase in cellular levels of the antioxidant 
enzyme, superoxide dismutase 1 (SOD1), following infection with RVFV.  
P53 phosphorylation is important for many cellular process including 
apoptosis and DNA damage signaling.  As DNA damage sensors play central 
roles in the cellular response to genotoxic stress and viral 
manipulation has been well characterized in other systems, we 
hypothesized that these pathways might be involved in RVFV pathogenicity 
and indeed found an NSs dependant induced phosphorylation at specific 
DNA damage signaling checkpoints following RVFV infection: p-ATM 
(Ser1981), p-Chk.2 (Thr68), p-H2A.X (Ser139)* *and p-P53 (Ser15), as 
well as concurrent S phase arrest.  Use of specific checkpoint 
inhibitors ATM and Chk.2 resulted in a marked decrease in S phase arrest 
as well viral production.  By identifying these cellular viral targets 
we hope to develop therapeutics targeted to the host, establishing a 
much broader range of targets with a decreased likelihood of viral 
adaptation.

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