Reprogramming the genetic code: The emerging role of ribosomal frameshifting in regulating cellular gene expression

Abstract

Reading frame maintenance is a critical property of ribosomes. However, a number of genetic elements have been described that can induce ribosomes to shift on mRNAs, the most well understood of which are a class that directs ribosomal slippage by one base in 5' (-1) direction. This is referred to as programmed -1 ribosomal frameshifting (-1 PRF). Recently, a new -1 PRF promoting element was serendipitously discovered in a study examining the effects of stretches of adenosines in the coding sequences of mRNAs. Here, we discuss this finding, recent studies describing how -1 PRF is used to control gene expression in eukaryotes, and how -1 PRF is itself regulated. The implications of dysregulation of -1 PRF on human health are examined, as are possible new areas in which novel -1 PRF promoting elements might be discovered. Also watch the Video Abstract.

Keywords: NMD; SCA26; cancer; frameshifting; miRNA; polyA track; pseudoknot; ribosome; ribosomopathy; telomere; translation.

Figure 1

Frameshifting on viral compared to cellular mRNAs. A: In viruses, PRF events result in synthesis of C‐terminally extended fusion proteins. In many virus families (e.g. Retroviridae, Totiviridae), rates of ‐1 PRF determine the stoichiometric ratios of capsid (pink Gag) to replicase (pink + blue Gag‐pol) proteins. Correct ratios are critical for viral particle assembly. B: Canonical “genomic” ‐1 PRF signals or poly(A) tracks (blue triangle) can direct an elongating ribosome to a ‐1 frame premature termination codon (PTC). The recognition of the PTC by the ribosome results in activation of nonsense mediated mRNA decay (NMD) pathway and subsequent degradation of the transcript through a process of decapping and deadenylation followed by exonucleolytic degradation by Xrn1p (5′→3′) and the Ski complex (3′→5′).

Figure 2

The relationship between frameshift efficiency and mRNA abundance. The mathematical relationship between ‐1 PRF efficiency and mRNA abundance was determined using frameshift signals derived from the yeast EST1, EST2, STN1, and CDC13 mRNAs. These were cloned into a reporter gene and cellular mRNA steady‐state abundances were plotted relative to the abundance of the reporter without frameshift signals. Plotting of these data fit to the logarithmic function f(x) = e^−0.05x (adapted from 22).

Figure 3

From genes to disease and points of therapeutic intervention. Mutations in genes that participate in translation that alter global rates of ‐1 PRF elicit downstream post‐transcriptional surveillance pathways e.g. NMD that alter the transcriptome. This leads to altered gene expression (proteomic changes) and progression to disease states. Therapeutic approaches may include use of synthetic polynucleotide analogs (miRNAs and related derivitives) targeting specific ‐1 PRF signals designed to fine tune frameshifting rates. Given the epistatic relationship of NMD to ‐1 PRF, targeting this pathway using small molecule inhibitors presents another therapeutic modality.