Objetivo dUTPases (DUTs) are enzymes that regulate cellular dUTP levels to prevent the misincorporation of uracil into DNA. Recently however, DUTs have been involved in the control of relevant cellular processes. How these regulatory functions are controlled remains unsolved. The recent elucidation of the mechanistic role of DUTs in the transfer of staphylococcal pathogenicity islands (SaPIs) by our group has revealed an entirely novel and surprising strategy involving DUTs in signalling. Namely, we have demonstrated that in addition to the 5 classical domains present in all the trimeric DUTs, staphylococcal phage-encoded DUT proteins possess an extra region (Motif VI) involved in SaPI de-repression by binding to the SaPI-encoded repressor (Stl). Although this domain is necessary, it does not suffice to induce the SaPI cycle. Unexpectedly, the strongly conserved DUT motif V is also inherently involved in mediating de-repression. Crystallographic and mutagenic analyses have demonstrated that binding to dUTP orders the C-terminal motif V of phage-encoded DUTs, potentially rendering these proteins in the conformation required for SaPI de-repression. In contrast, conversion into the apo state conformation by the hydrolysis of the bound dUTP disorders motif V and generates a protein that is unable to induce the SaPI cycle. Analogously, previous work demonstrated that the trimeric rat DUT interacts with the transcriptional factor PPARα, an interaction that depends on an “extra” N-terminal motif VI present in the DUT protein and requires the C-terminal domain contribution, strongly supporting in general the mechanism involving DUTs in signalling. In summary, our results suggest that DUTs define a widespread family of signalling molecules that acts analogously to eukaryotic G-proteins. This project stems from this ground-breaking result, and will investigate the biological role of DUTs as signalling molecules, opening up the possibility to establish dUTP as a new second messenger. Ámbito científico natural sciencesbiological sciencesmicrobiologybacteriologynatural sciencesbiological sciencesmicrobiologyvirologynatural sciencesbiological sciencesgeneticsDNAnatural sciencesbiological sciencesgeneticsgenomesviral genomesnatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsenzymes Palabras clave dUTPase signalling dUTP bacteriophage Staphylococcus aureus Enterococcus Toxoplasma Plasmodium Programa(s) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Tema(s) ERC-ADG-2014 - ERC Advanced Grant Convocatoria de propuestas ERC-2014-ADG Consulte otros proyectos de esta convocatoria Régimen de financiación ERC-ADG - Advanced Grant Institución de acogida IMPERIAL COLLEGE OF SCIENCE TECHNOLOGY AND MEDICINE Aportación neta de la UEn € 210 000,00 Dirección SOUTH KENSINGTON CAMPUS EXHIBITION ROAD SW7 2AZ LONDON Reino Unido Ver en el mapa Región London Inner London — West Westminster Tipo de actividad Higher or Secondary Education Establishments Enlaces Contactar con la organización Opens in new window Sitio web Opens in new window Participación en los programas de I+D de la UE Opens in new window Red de colaboración de HORIZON Opens in new window Coste total € 210 000,00 Beneficiarios (2) Ordenar alfabéticamente Ordenar por aportación neta de la UE Ampliar todo Contraer todo IMPERIAL COLLEGE OF SCIENCE TECHNOLOGY AND MEDICINE Reino Unido Aportación neta de la UEn € 210 000,00 Dirección SOUTH KENSINGTON CAMPUS EXHIBITION ROAD SW7 2AZ LONDON Ver en el mapa Región London Inner London — West Westminster Tipo de actividad Higher or Secondary Education Establishments Enlaces Contactar con la organización Opens in new window Sitio web Opens in new window Participación en los programas de I+D de la UE Opens in new window Red de colaboración de HORIZON Opens in new window Coste total € 210 000,00 UNIVERSITY OF GLASGOW Reino Unido Aportación neta de la UEn € 2 036 192,00 Dirección UNIVERSITY AVENUE G12 8QQ Glasgow Ver en el mapa Región Scotland West Central Scotland Glasgow City Tipo de actividad Higher or Secondary Education Establishments Enlaces Contactar con la organización Opens in new window Sitio web Opens in new window Participación en los programas de I+D de la UE Opens in new window Red de colaboración de HORIZON Opens in new window Coste total € 2 036 192,00