TnpB homologues exapted from transposons are RNA-guided transcription factors

Tanner Wiegand, Florian T. Hoffmann, Matt W. G. Walker, Stephen Tang, Egill Richard, Hoang C. Le, Chance Meers and Samuel H. Sternberg ()
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Tanner Wiegand: Columbia University
Florian T. Hoffmann: Columbia University
Matt W. G. Walker: Columbia University
Stephen Tang: Columbia University
Egill Richard: Columbia University
Hoang C. Le: Columbia University
Chance Meers: Columbia University
Samuel H. Sternberg: Columbia University

Nature, 2024, vol. 631, issue 8020, 439-448

Abstract: Abstract Transposon-encoded tnpB and iscB genes encode RNA-guided DNA nucleases that promote their own selfish spread through targeted DNA cleavage and homologous recombination1–4. These widespread gene families were repeatedly domesticated over evolutionary timescales, leading to the emergence of diverse CRISPR-associated nucleases including Cas9 and Cas12 (refs. 5,6). We set out to test the hypothesis that TnpB nucleases may have also been repurposed for novel, unexpected functions other than CRISPR–Cas adaptive immunity. Here, using phylogenetics, structural predictions, comparative genomics and functional assays, we uncover multiple independent genesis events of programmable transcription factors, which we name TnpB-like nuclease-dead repressors (TldRs). These proteins use naturally occurring guide RNAs to specifically target conserved promoter regions of the genome, leading to potent gene repression in a mechanism akin to CRISPR interference technologies invented by humans7. Focusing on a TldR clade found broadly in Enterobacteriaceae, we discover that bacteriophages exploit the combined action of TldR and an adjacently encoded phage gene to alter the expression and composition of the host flagellar assembly, a transformation with the potential to impact motility8, phage susceptibility9, and host immunity10. Collectively, this work showcases the diverse molecular innovations that were enabled through repeated exaptation of transposon-encoded genes, and reveals the evolutionary trajectory of diverse RNA-guided transcription factors.

Date: 2024
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DOI: 10.1038/s41586-024-07598-4

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