Non-canonical mechanisms of translation initiation and regulation

ABSTRACT My previous work showed specific mutations in mRNAs activate initiation at non-canonical start codons (e.g., GUG, ACG) resulting in expression of neurotoxic proteins that cause multiple human disorders. However, non- canonical translation is not restricted to atypical start codons or necessarily connected to pathology; cells rely on alternative mechanisms to respond to specific states to translate mRNAs with spatiotemporal precision. Our basic understanding of non-canonical translation is incomplete, and the long-term goal of this research program is to understand how and why non-canonical translation occurs in cells. We will fill gaps in our understanding of non-canonical initiation by addressing two fundamental questions. What mechanisms enable alternative initiation factors to support translation? Which aminoacyl tRNAs other than Met-tRNAiMet are used for initiation? Our previous and current work has also discovered unconventional translational regulatory mechanisms that use ribosome queuing and non-canonical RNA-binding domains (ncRBDs). We will establish how unconventional regulatory mechanisms such as ribosome queuing are used as cellular sensors of elongation to drive apoptosis, and how proteins with ncRBDs regulate translation. My research program will shed new light on how the translation machinery is used to create a diverse repertoire of initiation and regulatory mechanisms. In doing so, we will expand our understanding of the coding potential of the genome and how alterations in protein synthesis lead to human disease.