> 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. > > *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. > > ### > >