Changed in translation: mRNA recoding by −1 programmed ribosomal frameshifting

Abstract

Programmed S1 ribosomal frameshifting (S1PRF) is an mRNA recoding event commonly utilized by viruses and bacteria to increase the information content of their genomes. Recent results have implicated S1PRF in quality control of mRNA and DNA stability in eukaryotes. Biophysical experiments demonstrated that the ribosome changes the reading frame while attempting to move over a slippery sequence of the mRNA -when a roadblock formed by a folded downstream segment in the mRNA stalls the ribosome in a metastable conformational state. The efficiency of S1PRF is modulated not only by cis-regulatory elements in the mRNA but also by transacting factors such as proteins, miRNAs, and antibiotics. These recent results suggest a molecular mechanism and new important cellular roles for S1PRF.Accurate decoding versus programmed recoding Ribosomes (see Glossary) are cellular factories that produce proteins in all cells using the nucleotide sequence of mRNAs as a blueprint. Nucleotide triplets of an mRNAthe codons -are translated into an amino acid sequence of a protein. The selection of the translation start and the reading frame on an mRNA is tightly controlled during the initiation phase of protein synthesis. The subsequent elongation phase entails repeated cycles of codon decoding by aminoacyl-tRNA, peptide bond formation, and tRNAmRNA translocation. Elongation cycles continue until the ribosome reaches a stop codon, on which translation is terminated. It is intuitively clear that translation of an mRNA sequence into a protein must be colinear and highly accurate. Errors can lead to the formation of toxic or misfolded proteins, increase the energetic cost of translation, and cause additional load on the cellular clean-up and quality-control machineries [1]. To avoid this burden, cells have evolved sophisticated control mechanisms that ensure the fidelity of decoding and reading frame maintenance. However, in special cases, the ribosomes, guided by signals encoded in the mRNA, abandon the principle of mRNAprotein colinearity and read the message in an alternative way, which results in mRNA recoding (Box 1) [2][3][4].Programmed frameshifting is a recoding event that can occur in the + or À direction relative to the normal 0-frame mRNA translation by shifting the ribosome by one or two nucleotides, thereby producing two (or even three) different proteins from one mRNA. In contrast to spontaneous frameshifting, which is infrequent, the efficiency of programmed frameshifting may be as high as 80%, although in many cases it is only a few percent [5]. Programmed frameshifting increases the coding potential of the genome and is often used to expand the variability of cellular proteomes, adapt to changing environments, or ensure a defined stoichiometry of protein products. The mechanisms of +1 and À1 frameshifting appear to be different, and particularly the mechanism of À1 programmed ribosome frameshifting (À1PRF), its abundance, and physiological significance have remained unclear for a long time. The advances of biophysical techniqu...

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“…Many clinically relevant antibiotics target the ribosome, and induce errors in all stages of the decoding process. Furthermore, while programmed ribosomal frameshift (PRF) is exploited by some viruses (and their host cells) to control the amount of their structural and enzymatic proteins available for viral particle assembly (Brierley, 1995; Caliskan et al, 2015; Dinman, 1995; Dunkle and Dunham, 2015), slippage of ribosomes in either direction (5’ (−1) or 3’ (+1)) will produce a truncated protein, or lead to mRNA degradation via nonsense-mediated decay (Belew and Dinman, 2015). …”

Clarifying the Translational Pausing Landscape in Bacteria by Ribosome Profiling

“…SD motifs have well-characterized roles in frameshifting in bacteria: in the dnaX gene, an internal SD motif contributes to −1 frameshifting at a slippery sequence followed by an mRNA hairpin (Larsen et al, 1994). In vitro studies on this system have shown that the downstream hairpin blocks translocation (Caliskan et al, 2014; Chen et al, 2014), resulting in a kinetic pause; this in turn allows different codons and reading frames to be sampled on the slippery sequence (Caliskan et al, 2015; Yan et al, 2015). In the metastable state where the ribosome slips on the message, the SD motif stabilizes the interaction with the mRNA in a new position.…”

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