University of Florida

Well-established rules of translational initiation have been used as a cornerstone in molecular biology to understand gene expression and to frame fundamental questions about what proteins a cell synthesizes, how proteins work and to predict the consequences of mutations.  For a group of neurological diseases caused by the abnormal expansion of short segments of DNA (e.g. CAG/CTG repeats), mutations within or outside of predicted coding and non-coding regions are thought to cause disease by protein gain or loss-of-function or RNA gain-of-function mechanisms.  The research team unexpectedly discovered the canonical rules of protein translation do not apply for these repeats and in the absence of an ATG initiation codon, expanded CAG and CTG often express homopolymeric proteins in all three frames (e.g. polyGln, polyAla, polySer from CAG repeats).  This Repeat Associated Non-ATG translation (RAN translation) depends on RNA structure and repeat length and occurs when expansion constructs are integrated into mammalian brain.  Additionally, they showed that RAN translation occurs in two human CAG/CTG expansion diseases: DM1 and SCA8.  The project will pursue critical questions:  How does RAN translation work?  Is RAN translation a key, previously unrecognized cellular process?  Are repetitive sequences throughout the genome translated into proteins and if so, what is their function?