{"doi":"10.1101/2023.11.30.569447","title":"Emergence of RNA-guided transcription factors via domestication of transposon-encoded TnpB nucleases","abstract":"Abstract Transposon-encoded tnpB genes encode RNA-guided DNA nucleases that promote their own selfish spread through targeted DNA cleavage and homologous recombination 1–4 . This widespread gene family was repeatedly domesticated over evolutionary timescales, leading to the emergence of diverse CRISPR-associated nucleases including Cas9 and Cas12 5,6 . We set out to test the hypothesis that TnpB nucleases may have also been repurposed for novel, unexpected functions other than CRIS-PR-Cas. Here, using phylogenetics, structural predictions, comparative genomics, and functional assays, we uncover multiple instances of programmable transcription factors that we name TnpB-like nuclease-dead repressors (TldR). These proteins employ naturally occurring guide RNAs to specifically target conserved promoter regions of the genome, leading to potent gene repression in a mechanism akin to CRISPRi technologies invented by humans 7 . 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 motility 8 , phage susceptibility 9 , and host immunity 10 . Col-lectively, this work showcases the diverse molecular innovations that were enabled through repeated exaptation of genes encoded by transposable elements, and reveals that RNA-guided transcription factors emerged long before the development of dCas9-based editors.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":395423,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9417,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":856107,"name":"Florian T. Hoffmann","orcid":"0000-0003-0301-4259","position":1,"is_corresponding":false},{"id":737643,"name":"Matt W.G. Walker","orcid":"0000-0003-3345-8248","position":2,"is_corresponding":false},{"id":567165,"name":"Stephen Tang","orcid":"0000-0001-5492-9796","position":3,"is_corresponding":false},{"id":1170683,"name":"Egill Richard","orcid":"0000-0002-9776-6197","position":4,"is_corresponding":false},{"id":1170684,"name":"Hoang C. Le","orcid":"0009-0003-7911-881X","position":5,"is_corresponding":false},{"id":459642,"name":"Chance Meers","orcid":"0000-0003-2554-3987","position":6,"is_corresponding":false},{"id":561678,"name":"Samuel H. Sternberg","orcid":"0000-0001-8240-9114","position":7,"is_corresponding":false},{"id":226296,"name":"Tanner Wiegand","orcid":"0000-0002-0528-268X","position":0,"is_corresponding":true}],"reference_count":98,"raw_metadata":null,"created_at":"2026-07-19T01:19:22.857556Z","pmid":"38076855","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}