Protein trans-activation of ribosomal frameshifting: a new paradigm in gene expression. (360G-Wellcome-202797_Z_16_Z)

Programmed ribosomal frameshifting (PRF) is a translational control mechanism widely used in the regulated expression of many viral, and several cellular proteins. The mRNA signals that induce PRF comprise a slippery sequence, where the ribosome changes into an overlapping frame, and an essential, stimulatory RNA structure which promotes frameshifting by modulating the ribosomal elongation cycle. Recently, we have uncovered two novel examples of viral PRF signals where frameshifting is trans-activated through the action of viral (cardiovirus 2A, arterivirus nsp1beta) and cellular proteins (poly(C) binding protein). The discovery of such protein-stimulated PRF opens up a completely new area in this field and offers novel opportunities for the study of protein-ribosome interactions. Our aim is to characterise the trans-acting factors and the mechanism by which they induce these novel PRF events. This will be achieved through a combination of functional assays, RNA-protein and protein-protein interaction studies and structural biology. This work will provide important new insights into ribosome structure and function, gene regulation, protein-protein and protein-nucleic acid interactions, virus replication strategies and virus-host interactions.