Tuft cells are a uncommon chemosensory lineage that coordinates immune and neural responses to overseas pathogens in mucosal tissues1. Current research have additionally revealed tuft cell-like human tumors2,3, significantly as a variant type of small cell lung most cancers (SCLC). Each regular and neoplastic tuft cells share a genetic requirement for the transcription issue POU2F32,4, though the transcriptional mechanisms that generate this cell sort are poorly understood. Right here we present that binding of POU2F3 to the uncharacterized proteins C11orf53 and COLCA2 (renamed right here OCA-T1 and OCA-T2, respectively) is important within the tuft cell lineage. OCA-T1 and OCA-T2 are paralogs of the B cell-specific coactivator OCA-B, that are encoded in a gene cluster and harbor a conserved peptide that binds to class II POU transcription components and octamer motif DNA in a bivalent method. We show that binding between POU2F3 and OCA-T1 or OCA-T2 is important in tuft cell-like SCLC. As well as, we generated OCA-T1 knockout mice, that are viable however lack tuft cells in a number of mucosal tissues. These findings reveal the POU2F3-OCA-T advanced because the grasp regulator of tuft cell id and a outstanding molecular vulnerability of tuft cell-like SCLC.