Mechanisms and Regulation of Yeast Internal Ribosome Entry Sites

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My chief scientific interest is post-transcriptional regulation otgene expression. In particular, I am fascinated by the diversity and complexity of RNA-dependent mechanisms of translational control. In the future, I hope to make my own lab an outstanding center for research into the fundamental mechanisms of gene expression, and the defects in gene expression that lead to human diseases. Pursuing my training in Jennifer Doudna's lab at UC Berkeley will provide an outstanding technical education in biochemical dissection of RNA-protein interactions relevant to translation, as well as a diverse and stimulating intellectual environment. I will also develop the professional skills I will need to thrive as an independent investigator in the future, through numerous opportunities to supervise students with diverse scientific strengths and interests. Translation initiation is a crucial point of regulation of eukaryotic gene expression. In response to a variety of environmental insults, cells down-regulate the primary (cap-dependent) mechanism of translation while favoring expression of a select group of genes via alternative initiation mechanisms including direct recruitment of the translation machinery to internal ribosome entry sites (IRESs). Little is known about the molecular basis for cellular IRES activity or for message-specific regulation of these mechanisms. I have identified 24 yeast cellular IRES elements with strong activity both in vitro and in vivo, creating a unique opportunity to combine molecular genetics and biochemistry to determine the molecular basis for, and physiological significance of IRES-dependent gene expression.My aim is to define the molecular functions of cellular IRES RNA sequences and their associated RNA-binding proteins and ultimately, to identify the mechanisms linking stress-related signaling pathways to global and message-specific translational regulation using a combination of biochemical, molecular genetic, and bioinformatic approaches. Results from this work will provide detailed molecular insight into the mechanisms and regulation of internal initiation of translation by diverse cellular IRESs, which is expected to have wide-ranging implications for translational control of eukaryotic gene expression.