Ricerc@Sapienza

The perception of RNA–protein interactions is currently changing from a protein-centric approach, in which proteins regulate the expression and activity of RNA, to a more complex view, in which RNA molecules can directly regulate protein's function and thus cell behavior, in a process called riboregulation.
An expanding number of metabolic enzymes display a moonlighting function as RNA-binding proteins (RBPs) . Enzymes in glycolysis and citric acid cycle bind RNA, as well as enzymes from gluconeogenesis, amino acid biosynthesis, fatty acid oxidation, lipid and nucleotide metabolism. Strikingly, a prevalence of metabolic enzymes as RBPs was recently found in mammalian organs, as compared to cultured cells, with a large proportion of these enzymes containing cofactors such as NAD/NADP or co-substrates such as folates.

The wide occurrence and conservation of the RNA binding ability across the evolutionary tree suggest that RNA and riboregulation may play a significant and unexplored role in the modulation of intermediary metabolism . While changes in nutrient status, gene expression or epigenetic profile are known to control metabolic remodeling, the extent to which RNA-protein interactions contribute to this process is largely unknown. Existing examples suggest that the RNA binding ability is mainly exploited to control the translation of the target RNAs. However, the effects of RNA binding are likely wider: RNA may also affect other properties of an enzyme, such as activity, intracellular localization, interaction with substrates or cofactors, aggregation state and stability. Examples of RNA-protein interactions affecting protein function come from viral regulatory RNAs. Very recently, lncRNAs were shown to recruit chromatin-modifying enzymes at genomic sites, or act as a structural backbones to form a metabolon complex, likely facilitating catalytic efficiency by ‘‘channeling’’ of metabolites, or to enhance post-translational modifications of selected enzymes.

The mechanistic understanding on how these effector RNAs can modulate the function of enzymes is still very poor, since very few examples of detailed enzyme-RNA interactions are available. Moonlighting metabolic enzymes often do not contain any known RNA-binding domain which could aid the prediction of the binding site and mechanism of action. The features of the effector RNA are known for only some of the enzyme-RNA pairs, among the RBPs. RNA protein-complexes show high plasticity, indicating that weak interactions, a considerable degree of disorder and the formation of transient complexes are key features for many RNA–protein functional units.

Our team have a consolidated interest in the role of amino acid metabolism in cancer, and have pioneered the riboregulation field, by showing that the activity of the pyridoxal-5'-phosphate (PLP)-dependent enzyme serine hydroxymethyltransferase (SHMT) is modulated by an RNA .

We wish to identify an innovative class of RNA molecules, acting as allosteric modulators of metabolic enzymes, to be further developed into future therapeutic tools to fight cancer.
We aim at investigating aspects that are largely unexplored in the field of metabolic reprogramming in cancer, and we believe that our project will have a large impact of the RNA-therapeutic field. In addition, clarifying the molecular details of how RNA may regulate the function of a protein enzyme, will shed light on a more fundamental and fascinating issue, i.e. how RNA molecules might have concurred in the emergence of new metabolic abilities and to the shaping and regulation of metabolic routes.