Understanding the evolution of genomes and the regulation of the proteome.
We have discovered a new mechanism for protein synthesis control (Novoa et al., Cell 2012). More specifically, we have described the role of two tRNA anticodon modifications in genome evolution and proteome regulation across the complete tree of life. We have shown that these modifications contributed to the evolution of genomes, and currently play a part in the control of protein synthesis in extant species.
We have demonstrated that the codon composition of highly expressed genes is enriched in triplets recognized by modified tRNAs. Thus, a new mechanism for the control of gene expression arises based on the relationship between the codon composition of any given gene and the existing pool of modified tRNAs in the cell. We want to explore this relationship and characterize how levels of modified tRNAs may affect gene expression levels. For that purpose we have chosen two experimental models that represent extreme cases either in the levels of modification activity or in the numbers of tRNA genes in the genome.
More specificaly, we propose to study the biological significance of extreme variations in the levels of tRNAmodification that are reported between normal and transformed mammalian cells. On the other hand, we propose to study the biological role of these modifying enzymes in organisms that contain a dramatically simplified complement of tRNA genes. Specifically, we will be investigating their role in Plasmodium falciparum, the causing agent of malaria and the eukaryotic organisms with the simplest set of tRNA genes in its genome. Given the simplicity of tRNA gene composition, and the extreme codon usage bias of Plasmodium, we suspect that the function of tRNA modification is particularly important to allow a proper match between tRNA content and genetic codon composition.