| Summary: | <p>Deoxynucleoside triphosphates (dNTPs) are the building blocks of DNA. DNA synthesis requires dNTPs for replication and subsequent cell division. Therefore, nucleotide metabolism in cells is tightly regulated and failure of this regulation results in damage, toxicity and cell death. SAMHD1 is a highly conserved protein that degrades dNTPs and restricts HIV-1 through dNTP starvation. SAMHD1 is mutated in Aicardi-Goutières syndrome, a disease characterised by the chronic production of type I interferon. SAMHD1 is also involved in DNA repair and is mutated in cancer. SAMHD1 evolved before lentiviruses, suggesting that SAMHD1’s main function is not to restrict viruses. This project aimed to identify and characterise SAMHD1’s ancestral function. I show that addition of deoxynucleosides (dNs) to the culture medium resulted in the death of SAMHD1-deficient cells but not of WT cells. dNs were taken up by the cells and converted into dNTPs through the nucleotide salvage pathway. Cell death was most pronounced upon feeding with deoxyguanosine (dG) alone, suggesting that dGTP overload is particularly toxic to cells. In this model SAMHD1 tunes dNTP levels and protects cells against apoptosis triggered by dNTP overload or imbalances in the dNTP pools. Characterisation of this mechanism shed light on the mechanism of action of forodesine, an anti-cancer agent that inhibits purine nucleoside phosphorylase. Forodesine induces the accumulation of dGTP and subsequent cell death. Nevertheless, forodesine showed efficacy only in a minority of leukaemic patients, for unknown reasons. PBMCs from CLL patients with SAMHD1 loss-of-function mutations showed a significant reduction of CLL B-cells upon treatment with forodesine and dG compared with the control group. Therefore, I propose a model where SAMHD1 limits the efficacy of the PNP inhibitor forodesine which predict that patients with SAMHD1 mutations respond well to forodesine treatment. Forodesine could be used as a precision medicine. This new important role of SAMHD1 in dealing with dNTP overload and unbalances may be SAMHD1’s ancestral function. This mechanism can be exploited physiologically where dNTP accumulation is required for toxicity, such as forodesine treatment.</p>
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