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
	     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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