Elevation of Intracellular dNTP Levels: A Mechanistic Role of SAMHD1 Cancer Mutations

Elevated intracellular dNTP level is a biochemical marker of cancer cells. Recently, a series of mutations in a highly multi-functional dNTPase, SAMHD1, have been reported in various cancers. Here we investigated the role of SAMHD1 in cancer by characterizing cancer-specific SAMHD1 mutations. R366C/H mutants, which were found in two cancer types, lost dNTPase activity and their X-ray structures demonstrate the absence of dGTP substrate in their active site, likely due to loss of interaction with γ-phosphate of the substrate. The R366C/H mutants failed to reduce intracellular dNTP levels and restrict HIV-1. However, these mutants retain dNTPase-independent functions including mediating dsDNA break repair, interacting with CtIP and Cyclin A2, and suppressing innate immune responses.Finally, SAMHD1 degradation in human primary activated/dividing CD4+ T cells further elevates cellular dNTP levels. This study supports that the loss of SAMHD1 dNTPase activity mechanistically contributes to the elevated dNTP levels commonly found in cancer cells.