Research InterestsAll living cells must coordinate their metabolism, growth, division, and differentiation with their gene expression. Gene expression is regulated at multiple layers, from histone modifications (histone code) through RNA processing to protein degradation. While most layers are extensively studied, the regulatory role of specialized ribosomes (ribosome code) is largely unexplored. Such specialization has been suggested by the observation that mutations of ribosomal proteins (RPs) can cause diseases, such as cancer and Diamond Blackfan anemia, and can affect selectively the synthesis of some proteins but not of others. This selectivity raises the hypothesis that cells may build specialized ribosomes with different stoichiometries among RPs as a means of regulating protein synthesis.
While the existence of specialized ribosomes has been hypothesized for decades, experimental and analytical roadblocks (such as the need for accurate quantification of homologous proteins and their modifications) have limited the evidence to only a few examples, e.g. the phosphorylation of RP S6. I developed methods to clear these roadblocks and obtained direct evidence for variable stoichiometry among core RPs in unperturbed yeast and mammalian stem cells and its fitness phenotypes. I aim to characterize ribosome specialization and its coordination with gene regulation, metabolism, and cell growth and differentiation. I want to understand quantitatively, conceptually, and mechanistically this coordination with emphasis on direct precision measurements of metabolic and protein translation and degradation rates in absolute units, molecules per cell per hour.