dUTPases (Duts) are assumed to be ubiquitous enzymes regulating cellular dUTP levels to prevent misincorporation of uracil into DNA. Surprisingly for an enzyme encoded in the host genome, several viruses, including different phages, codified for their own copy of Dut. Recently however, Duts have been involved in the control of several relevant cellular processes, suggesting that they perform regulatory functions and explaining their presence in phage genomes. This signalling capacity is exemplified by the trimeric and dimeric staphylococcal phage Duts. We have showed that the trimeric staphylococcal phage encoded Duts are signaling molecules that act analogously to eukaryotic G-proteins, using dUTP as a second messenger. These Duts induce the cycle of some Staphylococcal pathogenicity islands (SaPIs) by binding to the SaPI coded Stl repressor. To perform this regulatory role, the trimeric Duts require their characteristic extra motif VI, only present in the staphylococcal phage coded trimeric Duts, as well as two additional conserved catalytic domains present in all trimeric Duts. In the Dut:Stl interaction the nucleotide will work as a switcher, since the apo Dut form recognizes the Stl repressor while the dUTP bound form will blocks the interaction. Interestingly, dimeric staphylococcal phage Duts, which lacks these motifs, are also able to interact with Stl and induce SaPI cycle, opening new questions about the regulatory mechanism of Duts. Using different approaches in vivo and in vitro we are trying to shed light on this question, deciphering the molecular basis of Dut-Stl interaction and, therefore, the mechanism by which the Duts perform regulatory functions. Our current findings in this topic will be discussed in the presentation. In addition and since SaPI derepression by the Duts is deleterious for phage reproduction, it is obvious that Duts should play an important role for the phage cycle that imposes its conservation as we will discuss in the presentation.