Structural and genetic dissection of RNA-guided gene repression by TnpB-derived transcription factors
TnpB nucleases, the evolutionary progenitors of CRISPR-associated Cas12 enzymes, are transposon-encoded, RNA-guided endonucleases found throughout bacteria. Independent of the trajectory towards adaptive immunity, TnpB nucleases have also recurrently given rise to TnpB-like nuclease-dead repressors (TldRs), a family of programmable RNA-guided transcription factors, though the physiological roles…
RNA-guided gene repression by TnpB-derived transcription factors, the evolutionary descendants of CRISPR-associated Cas12 enzymes, has been discovered to regulate bacterial peptide import machinery. TnpB nucleases, originally transposon-encoded RNA-guided endonucleases, have given rise to TldRs, a family of programmable transcription factors whose physiological roles are largely unknown.
A study identified a TldR clade associated with bacterial ABC transporter operons, which was found to repress the oligopeptide permease (opp) binding protein OppA in Enterococcus faecalis. This repression mechanism, involving a conserved bilobed architecture and TAM recognition inherited from TnpB ancestors, suggests that TldRs can selectively tune transporter composition by shaping the substrate repertoire of bacterial peptide import machinery.
The study's findings define the structural, genetic, and evolutionary basis of this widespread RNA-guided regulatory system, which has been domesticated from mobile genetic elements.
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