The ribosome: mechanisms of function, drug target and disease

The ribosome is the essential macromolecular complex of protein synthesis in all living cells. Different steps in translation are targeted by anti-infective agents, including such diverse drugs as aminoglycosides, macrolides, and spectinamides. In spite of decades of use of ribosomal drugs we still do only in part understand the principles which impact on the specificity, selectivity and toxicity of these agents. A detailed understanding of the mechanisms involved in resistance towards drugs targeting protein synthesis has long been hampered by the observation that rrn resistance mutations in general are recessive and that bacteria harbour multiple rRNA operons in their chromosome.

 

Mutations in mitochondrial ribosomal nucleic acids have been associated with human disease. However, experimental investigations on rRNAs in higher eukaryotes are complicated by the presence of several hundred copies of chromosomal rrn genes encoding ribosomal RNA. The multiplicity of genes encoding cytosolic and mitochondrial rRNAs in higher eukaryotes combined with the peculiarities of mitochondrial genetics have frustrated any attempt of genetic manipulation. In the laboratory we use a variety of techniques including genetics, microbiology, biochemistry, cell biology, and animal models to study mechanisms of ribosome function. This is done with the view to understand ribosome- associated diseases, to assess the determinants of antibiotic selectivity and drug specificity, and to understand the mechanisms of drug-associated toxicity.

 

Starting from our work on mistranslation-inducing aminoglycosides, we have more recently become interested to study how mammalian cells mitigate the deleterious effects of protein synthesis errors. Proteins are the building blocks and major signalling molecules of cells, and their synthesis and degradation are tightly regulated. Fidelity of protein synthesis and proper folding of proteins are central to the ability of living organisms to efficiently and accurately translate genomic information into functional proteins. Eukaryotic cells have various quality control systems and clearing mechanisms in place to maintain protein homeostasis. In addition to studying mechanistic and functional details of protein translation and degradation, we apply whole genome transcriptomic, metabolomic, and proteomic approaches towards an integrative study of the cellular response to mistranslation.