Ricerc@Sapienza

One of the most important metabolisms altered in cancer cells is One Carbon Metabolism (OCM), a complex network fuelling the synthesis of nucleotides, NADPH and methylation factors, exploitable by cancer cells to grow and proliferate without control. Serine hydroxymethyltransferase (SHMT) is an enzyme known to play a crucial role in OCM: it catalyses the reversible conversion of serine and tetrahydrofolate into glycine and 5,10 methylenetetrahydrofolate. Moreover, in my group during last years, a new characteristic of this protein came out: it¿ s not only a metabolic enzyme, but it is also a moonlighting protein, in fact it has the ability to bind nucleic acid (DNA and RNA). SHMT1 has the ability to bind and regulate the expression of its mitochondrial isoform by binding to the 5¿ untranslated region of the SHMT2 transcript (UTR), regulating its expression. We also observed that this RNA binding selectively inhibits the SHMT1 enzymatic activity: the conversion of serine to glycine is significantly affected in presence of inhibitory RNA sequences. These results suggest that the RNA-mediated inhibition may contribute to the control of serine consumption by SHMT1. Although several molecules have been proposed and tested in the past years, unfortunately at the moment there aren¿t SHMT inhibitors that can be successfully used in vivo, for this reason our aim is to find a completely new approach. Due to the capability of RNA binding, our goal is to test specific RNA sequences as SHMT inhibitors. The results emerging from this study could be so useful for the development of new nucleic acid- based inhibitors of SHMT, providing a novel chemotherapy strategy.