Dottorato in BIOCHIMICA

Titolo della tesi: "Deciphering and Reshaping the Role of SHMT: Unveiling its Multifaceted Functions in Metabolism and Genome Maintenance”

In the past, molecular biology was shaped by the notion of each gene encoding a single protein with a unique cellular function, a concept encapsulated in Norman Horowitz's "one gene-one enzyme-one function hypothesis." However, subsequent research unveiled the complexity of gene expression, revealing that a single gene can produce multiple proteins, each with distinct functions. Serine hydroxymethyltransferase (SHMT) is an eloquent example of this cellular versatility. It exhibits multifunctionality by catalyzing metabolic reactions crucial for cellular growth while also regulating other cellular processes such as genomic integrity. In particular, it is involved in the reversible conversion of serine and tetrahydrofolate, into glycine and N5,N10- Methylenetetrahydrofolate. This reaction is a part of a complex network of metabolic pathways, the one carbon metabolism (OCM), that fuels cancer growth and cell proliferation. Consequently, SHMTs are overexpressed in several types of tumors, being an interesting target for cancer therapy. In addition to having a catalytic activity, it has shown SHMT1 also has nucleic acids binding affinity. In cytosol SHMT1 binds SHMT2 transcript 5’UTR, through which negatively regulates SHMT2 expression and in turn serine to glycine reaction, catalyzed by SHMT1, is negatively riboregulated by the 5'UTR mRNA. Furthermore, SHMT1 translocate into the nucleus during S and G2/M phase or in response to DNA damage, to form a protein complex with DHFR and TYMS for de novo thymidylate biosynthesis in situ Therefore, this thesis explores SHMT's diverse roles, focusing on its non-canonical RNA/DNA binding properties and the resulting effects on cellular metabolism and genome maintenance. Moreover, our research sheds light on the potential therapeutic implications of targeting SHMT, paving the way for innovative approaches in cancer treatment and other pathologies.