The candidate has extensive training in the field of cancer virology and plans to extend her expertise in the field of biochemistry over the next 1-2 years as a postdoctoral fellow before transitioning into an independent faculty position at a major research institution. There, she aspires to make significant contributions to the field of human tumor virology and continue as an active participant in the training of future scientists. The UCSF medical center is an outstanding facility for biomedical research;it attracts world-class seminar speakers and provides an excellent forum for interaction and collaboration with a large variety of scientists who are world leaders in molecular biology and virology. Kaposi's sarcoma (KS) is the most common malignancy associated with untreated human immunodeficiency virus infection and is caused by a novel human herpesvirus, termed KSHV. During lytic replication, the virus induces a robust shutoff of nearly all cellular gene expression. This host shutoff is mediated by a protein conserved across the herpesvirus family but which has acquired a novel mRNA degradation function specific to KSHV. This proposal aims to reveal the mechanisms by which this viral protein promotes global cellular mRNA turnover through evaluation of the contribution of cellular mRNA degradation pathways and proteins to the host shutoff phenotype. Intriguingly, a small number of cellular genes escapes this virus-induced degradation, indicating that these genes likely play a critical role in KSHV biology. The specific sequence elements that confer protection to these escapees will be mapped and the mechanism by which they confer resistance will be investigated. In addition, the requirement for these cellular genes in the KSHV lifecycle will be determined by monitoring the progress of virus infection in their absence. Finally, the ability of gammaherpesviruses closely related to KSHV to promote host shutoff will be examined to assess the importance of this phenotype in similar human and non-human pathogens. The experiments designed herein to reveal how a single KSHV-encoded protein shuts down expression of nearly all cellular genes will provide valuable insight into how infection by this human tumor virus can progress to malignancy, and hopefully give us new clues for preventing the disease. In addition, knowledge generated from this research may extend to other cancer-associated human herpesviruses and provide key insight into their complex biology.