SAMHD1, a new regulator of DNA replication involved in Aicardi-Goutières syndrome

The stability of genetic information depends on the accuracy of DNA synthesis and the presence, at the right time, of appropriate amounts of DNA building blocks (dNTPs). Both nuclear and mitochondrial DNA synthesis may be affected by deficiency or surplus of dNTPs, leading to mutations and genetic diseases. Size and composition of the cellular dNTP pools are controlled by the combined action of synthetic and catabolic enzymes. Genetic deficiencies in some components of this enzyme network are associated to human diseases ranging from mitochondrial syndromes to severe immune deficiencies. Our work aims at understanding how inactivation of individual enzymes translates into pathologies. In cultured human cells we study how the enzyme network controlling dNTP pools reacts to enzyme mutations and which are the consequences for the stability of nuclear and mitochondrial DNA. Our project is centred on SAMHD1, a new enzyme that degrades the dNTPs. Mutations in its gene cause, through a mechanism still unknown, the severe autoimmune Aicardi-Goutières syndrome. Moreover, the enzyme acts as an inhibitor of viral infection. We found that SAMHD1 activity changes in different phases of a cell's life. To better understand how SAMHD1 regulates the dNTP pools we modify experimentally the cellular level of the enzyme in normal cells or use SAMHD1-deficient cells, provided by a British hospital. Then we analyse the alterations of dNTP pools and their effects on nuclear and mitochondrial DNA synthesis. So far we observed that SAMHD1 inactivation increases dNTP concentrations and prevents cycling cells from starting nuclear DNA replication but avoids mitochondrial DNA depletion in patient cells, suggesting an important role of SAMHD1 in the regulation of DNA synthesis.