Mechanisms and implications of programmed translational frameshifting

While ribosomes must maintain translational reading frame in order to translate primary genetic information into polypeptides, cis-acting signals located in mRNAs represent higher order information content that can be used to fine-tune gene expression. Classes of signals have been identified that direct a fraction of elongating ribosomes to shift reading frame by one base in the 5' (-1) or 3' (+1) direction. This is called programmed ribosomal frameshifting (PRF). Although mechanisms of PRF differ, a common feature is induction of ribosome pausing, which alters kinetic partitioning rates between in-frame and out-of-frame codons at specific 'slippery' sequences. Many viruses use PRF to ensure synthesis of the correct ratios of virus-encoded proteins required for proper viral particle assembly and maturation, thus identifying PRF as an attractive target for antiviral therapeutics. In contrast, recent studies indicate that PRF signals may primarily function as mRNA destabilizing elements in cellular mRNAs. These studies suggest that PRF may be used to fine-tune gene expression through mRNA decay pathways. The possible regulation of PRF by noncoding RNAs is also discussed.