Lost in Translation: When the Rules Do Not Apply

ABSTRACT Eukaryotic gene expression is strictly controlled and regulated during translation. For eukaryotic mRNAs, canonical cap‐dependent translation is the preferred pathway to synthesize proteins and starts with the recruitment of eukaryotic initation factors and the ribosome to the 5′ m 7 G cap structure of the mRNA, followed by ribosome scanning and AUG recognition. Canonical translation can however be impaired during cellular responses to certain environmental factors, including stress, viral infection, and hypoxia. In response to these conditions, cells shut down the canonical translation initiation pathway and utilize alternative translation initiation mechanisms some of which are heavily dependent on RNA secondary structures. One such non‐canonical initiation mechanism is mediated through Internal Ribosome Entry Sites (IRESs), found in viral and cellular mRNAs, which directly recruit the ribosome and do not require all translation initiation factors. Repeat‐associated non‐AUG (RAN) translation is another form of non‐canonical translation initiation shown to heavily rely on RNA structure: this mode of translation initiation is relevant in the context of a subset of neurological diseases. This review focuses on the role of RNA structure in noncanonical translation initiation mechanisms, with a focus on IRES‐mediated and RAN translation. This article is categorized under: Translation > Mechanisms Translation > Regulation RNA Structure and Dynamics > RNA Structure, Dynamics and Chemistry