The why, how, and when of bacterial ribosome rescue

mRNA translation by ribosomes is a rapid and accurate process, crucial to all life forms. However, sometimes ribosomes stall irreversibly in the coding region of the mRNA (a.k.a. No-Go), e.g. due to damaged mRNA, or at the 3’ end of the mRNA (a.k.a. Non-Stop), e.g. due to readthrough of a stop codon.

This may lead to potentially harmful peptides being made, and may also deplete the cells of ribosomes. Hence, ribosome rescue mechanisms have evolved in all branches of life.

We aim to connect the mechanistic details of these rescue systems, acquired from e.g. structural and biochemical research in reconstituted systems, with cell physiology.A new PhD student together with an experienced researcher will use our fluorescence-based system for single-molecule tracking to study the dynamic interplay between rescue factors and stalled ribosomes directly inside living bacterial cells.

Rescue of Non-Stop ribosomes can be studied immediately (years 1-2) since we already have the main factor, tmRNA, functionally labelled.

To study rescue of No-Go ribosomes (years 2-4), we need to finalize our new click-chemistry-based labelling approach (years 1-2).Ribosome rescue factors are involved in antibiotic tolerance.

Since the main bacterial ribosome rescue factors do not share homologs in eukaryotic cells, the bacterial rescue mechanisms have been pointed out as promising targets for new antibiotic drugs. With our unique experimental and analytical system, we can aid in this development.