biostudies-literatureHerzog DDeutsche ForschungsgemeinschaftEuropean Research Council8613-8623https://www.ebi.ac.uk/biostudies/studies/S-EPMC9121386biostudies-literatureUnknown144(19)The tumor suppressor protein <i>fragile histidine triad</i> (Fhit) is known to be associated with genomic instability and apoptosis. The tumor-suppressive function of Fhit depends on the interaction with the alarmone diadenosine triphosphate (Ap₃A), a noncanonical nucleotide whose concentration increases upon cellular stress. How the Fhit-Ap₃A complex exerts its signaling function is unknown. Here, guided by a chemical proteomics approach employing a synthetic stable Fhit-Ap₃A complex, we found that the Fhit-Ap₃A complex, but not Fhit or Ap₃A alone, impedes translation. Our findings provide a mechanistic model in which Fhit translocates from the nucleolus into the cytosol upon stress to form an Fhit-Ap₃A complex. The Fhit-ApJournal of the American Chemical SocietyChemical Proteomics of the Tumor Suppressor Fhit Covalently Bound to the Cofactor Ap₃A Elucidates Its Inhibitory Action on Translation.PMC9121386MA 2288 / 19-1STE 2517/1-1ERC-AdG 101019280101019280Mißun MDiederichs KJansen JStengel FMarx AHerzog DfalseChemical Proteomics of the Tumor Suppressor Fhit Covalently Bound to the Cofactor Ap₃A Elucidates Its Inhibitory Action on Translation.The tumor suppressor protein <i>fragile histidine triad</i> (Fhit) is known to be associated with genomic instability and apoptosis. The tumor-suppressive function of Fhit depends on the interaction with the alarmone diadenosine triphosphate (Ap₃A), a noncanonical nucleotide whose concentration increases upon cellular stress. How the Fhit-Ap₃A complex exerts its signaling function is unknown. Here, guided by a chemical proteomics approach employing a synthetic stable Fhit-Ap₃A complex, we found that the Fhit-Ap₃A complex, but not Fhit or Ap₃A alone, impedes translation. Our findings provide a mechanistic model in which Fhit translocates from the nucleolus into the cytosol upon stress to form an Fhit-Ap₃A complex. The Fhit-Ap2022-01-01T00:00:00Z2022 May2026-04-08T17:27:47.407Z2024-11-21T02:17:15.21ZS-EPMC91213863552278210.1021/jacs.2c00815