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Ribosome collisions alter frameshifting at translational reprogramming motifs in bacterial mRNAs

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Significance Ribosomes move along mRNAs in 3-nucleotide steps as they interpret codons that specify which amino acid is required at each position in the protein. There are multiple examples of… Click to show full abstract

Significance Ribosomes move along mRNAs in 3-nucleotide steps as they interpret codons that specify which amino acid is required at each position in the protein. There are multiple examples of genes with DNA sequences that do not match the produced proteins because ribosomes move to a new reading frame in the message before finishing translation (so-called frameshifting). This report shows that, when ribosomes stall at mRNA regions prone to cause frameshifting events, trailing ribosomes that collide with them can significantly change the outcome and potentially regulate protein production. This work highlights the principle that biological macromolecules do not function in isolation, and it provides an example of how physical interactions between neighboring complexes can be used to augment their performance. Translational frameshifting involves the repositioning of ribosomes on their messages into decoding frames that differ from those dictated during initiation. Some messenger RNAs (mRNAs) contain motifs that promote deliberate frameshifting to regulate production of the encoded proteins. The mechanisms of frameshifting have been investigated in many systems, and the resulting models generally involve single ribosomes responding to stimulator sequences in their engaged mRNAs. We discovered that the abundance of ribosomes on messages containing the IS3, dnaX, and prfB frameshift motifs significantly influences the levels of frameshifting. We show that this phenomenon results from ribosome collisions that occur during translational stalling, which can alter frameshifting in both the stalled and trailing ribosomes. Bacteria missing ribosomal protein bL9 are known to exhibit a reduction in reading frame maintenance and to have a strong dependence on elongation factor P (EFP). We discovered that ribosomes lacking bL9 become compacted closer together during collisions and that the E-sites of the stalled ribosomes appear to become blocked, which suggests subsequent transpeptidation in transiently stalled ribosomes may become compromised in the absence of bL9. In addition, we determined that bL9 can suppress frameshifting of its host ribosome, likely by regulating E-site dynamics. These findings provide mechanistic insight into the behavior of colliding ribosomes during translation and suggest naturally occurring frameshift elements may be regulated by the abundance of ribosomes relative to an mRNA pool.

Keywords: translational reprogramming; collisions alter; ribosome collisions; reprogramming motifs; alter frameshifting; frameshifting translational

Journal Title: Proceedings of the National Academy of Sciences of the United States of America
Year Published: 2019

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