Protein oxidation increases SAMHD1 binding ssDNA via its regulatory site

SAMHD1 dNTP hydrolase activity places it at the crossroad of several important biological pathways, such as viral restriction, cell cycle regulation, and innate immunity. Recently, a dNTPase independent function for SAMHD1 in homologous recombination (HR) of DNA double-strand breaks has been identified. SAMHD1 function and activity is regulated by several post-translational modifications, including protein oxidation. Here, we showed that oxidation of SAMHD1 increases ssDNA binding affinity and occurs in a cell cycle-dependent manner during S phase consistent with a role in HR. We determined the structure of oxidized SAMHD1 in complex with ssDNA. The enzyme binds ssDNA at the regulatory sites at the dimer interface. We propose a mechanism that oxidation of SAMHD1 acts as a functional switch to toggle between dNTPase activity and DNA binding.

Automated summary

The dNTP hydrolase activity of SAMHD1 places it at the center of important biological pathways such as viral restriction, cell cycle regulation, and innate immunity. Recently, it has been discovered that SAMHD1 also plays a role in homologous recombination (HR) of DNA double-strand breaks independent of its dNTPase activity. Several post-translational modifications, including protein oxidation, regulate the function and activity of SAMHD1. In this study, we found that oxidation of SAMHD1 increases its affinity for ssDNA and occurs in a cell cycle-dependent manner during S phase, suggesting its involvement in HR. We determined the structure of oxidized SAMHD1 in complex with ssDNA and proposed a mechanism where oxidation acts as a functional switch between dNTPase activity and DNA binding.