Regulation of nucleotide synthesis in normal and cancer cells

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Mammalian cells can produce nucleosides and nucleotides either by synthesis of these molecules from smaller precursors or through salvage pathways. Firstly, purine and pyrimidine bases can be synthesized from smaller precursors (de novo synthesis) and this process is known to be regulated by growth signals. Additionally, the salvage pathway can convert free purines and pyrimidines into nucleotides. Understanding the regulation of the nucleotide pathways by oncogenes will be vital to uncover new strategies to target cancer cell proliferation. Indeed, in addition to its demands for oxygen and nutrients, a tumor also requires nucleotides to survive and proliferate. Our laboratory aims to know whether the pyrimidine or the purine salvage pathway plays a role in cancer cell proliferation. A deficiency in de novo nucleotide synthesis (Purine or pyrimidine) will not only affect DNA and RNA synthesis, but also cell energy, ribosome biogenesis and levels of phospholipids, cytoskeleton function and glycosylation. In order to determine the contribution of the salvage and de novo nucleotide synthesis pathways in tumor metabolism, transformed cells, cancer cell lines and tumor mouse model will be used and metabolic flux through nucleotide metabolic pathways will be assessed.