> Reminder: 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.
> 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.
> ###