Dear all,Please not that the seminar room has been changed to BRB room 1001 (10th floor). BRB II/III 301 is not available at 5:30 pm this Friday. I’m sorry for any inconvenience and appreciate Drs. Jungsun Kim and Byung Chul Jeong for their kind help to reserve the seminar room. Have a nice day.Yours,Taeju
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Functional Characterization of a DNA Damage Response Network in Glioblastoma Associated with Long-Term Patient Survival
Taewon Yoon, PhD
Department of Radiation Oncology & Abrams Family Cancer Research Institute, University of Pennsylvania
Glioblastoma Multiforme (GBM) is the most aggressive primary brain cancer in humans with a median survival of less than 14 months. However, a small minority of GBM patients have a median survival of over three years. In an effort to identify genetic and epigenetic events that might explain this relative long-term survival, an integrative genomic approach was utilized. We show that in contrast to most GBM patients, relative long-term survivors have tumors that lack a biological network that responds to DNA damage. This network is comprised of pro-inflammatory genes and genes normally regulated through interferon signaling. By overlaying the network with phenotype information, key genes and gene-gene interactions that strongly associate with patient survival were identified to facilitate the discovery of important genes and genetic dependencies in the network. One such gene is an ubiquitin-like protein, Interferon-Stimulated Gene 15(ISG15), which is part of the interferon subnetwork. Targeted disruption of ISG15 in various GBM cell lines unmasked a DNA damage response as characterized by delayed S-phase entry and G2/M accumulation, increased gH2AX, and senescence. Various genes that displayed a predicted interaction with ISG15 were tested for evidence for a biological interaction. Functional validation confirmed that these predicted interactions with ISG15 were mirrored by genetic and regulatory interactions that resulted in rescue of the effects of ISG15 knockdown. In summary, we have identified a biological network that responds to and regulates DNA damage. The absence of network genes results in susceptibility to DNA damage, senescence, and decreased invasion. GBM patients with tumors lacking the network are rare long-term survivors of an otherwise uniformly and rapidly fatal tumor.
