Grant: Operating Grant

Viruses have evolved strategies to infect host cells and disrupt normal cellular functions while hijacking critical host machinery to express viral genes. All viruses proceed through an important stage during their life cycle called translation where viral proteins are expressed from a viral RNA. Some viruses such as poliovirus and Hepatitis C use a translation mechanism called an Internal Ribosome Entry Site or IRES for expressing their proteins. This IRES mechanism is not only important for viruses but also for cellular genes, including those involved in cancer. Therefore, elucidating IRES mechanisms is crucial for understanding a fundamental process of gene expression. Currently, IRES mechanisms are poorly understood. To gain insight, we will characterize the simplest IRES found to date, within the dicistroviridae family. Using biochemical techniques, we will identify how this IRES interacts with and hijacks the host cell's machinery. This IRES is functional in many systems including yeast and human cells, indicating that this unprecedented mechanism is conserved and that specialized cellular genes may also use this mechanism. Using genomic methods, we will identify cellular conditions when this viral IRES mechanism is used, thus revealing situations that are conducive for viral expression. Moreover, using this knowledge, we can search for cellular genes that also use this mechanism for gene expression. This proposal will not only shed light into the biological significance of this novel viral IRES mechanism but also provide a framework for understanding other viral and cellular IRES mechanisms in general.