Abstract
RNA molecules are frequently modified post-transcriptionally, and these modifications are required for proper RNA functions. To date, about 150 different types of chemical modifications have been identified in various RNA molecules across all domains of life. There are still a number of novel modifications to be discovered. RNA modifications appear to confer chemical diversities to simple RNA molecules basically composed of four letters, to acquire a greater variety of biological functions. These modifications play critical roles in stability and functions of RNA molecules. We've been carrying out a project to identify novel RNA modifications from various sources, and reported seven modifications so far. Taking advantage of mass spectrometric analysis of RNA modifications, we systematically screened a series of knockout strains for uncharacterized genes, and identified more than 40 genes responsible for tRNA modifications, rRNA modifications as well as mRNA modification. Recently, we identified a cap-specific adenosine methyltransferase (CAPAM) responsible for N6-methylation of m6Am at the transcription start site of eukaryotic mRNAs. It has been generally thought that tRNA modifications are stable and static, and their frequencies are rarely regulated. We previously reported that lack of tRNA modification causes major classes of mitochondrial diseases including MELAS and MERRF. Deficient tRNA modification results in defective protein synthesis, leading to mitochondrial dysfunction. These findings provided the first evidence of human disease caused by an RNA modification disorder. We call “RNA modopathy” as a new category of human diseases. I am going to show our recent studies on RNA modifications associated with human diseases and their dynamic regulation by sensing intracellular metabolites under physiological condition.
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