{"doi":"10.1093/nar/gkaf1018","title":"Functional microRNA targeting without seed pairing","abstract":"MicroRNAs (miRNAs) associate with Argonaute (AGO) proteins to serve as guides, directing binding to partially complementary sites in mRNAs, ultimately causing post-transcriptional repression. Complementarity to the miRNA seed (miRNA nucleotides 2-7) is typically necessary and sufficient for repression. Here, we investigate unusual sites with extensive complementarity to the miRNA 3' region (nucleotide 9 and onwards) but without complementarity to the seed. The top examples of these 3'-only sites bind as well as top canonical sites and impart similar repression, which can be further boosted by as few as 2-3 additional pairs to the miRNA seed. Despite these similarities, 3'-only sites have slower association and dissociation rates than seed-matched sites. They also impart different conformations to bound AGO-miRNA complexes than do seed-matched sites, and individual miRNAs differ substantially with respect to how well they bind their respective 3'-only sites. Thus, pairing to the seed is not always required for binding and repression, or for a target to gain access to the 3' region of the guide. For miRNAs that recognize 3'-only sites, those sites are estimated to constitute <1% of the set of endogenous target sites, a proportion resembling that of other rare but functional site types such as 3'-compensatory sites.","journal":"Nucleic Acids Research","year":2025,"id":522231,"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":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9582,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":990134,"name":"Peter Y. Wang","orcid":"0000-0002-6129-2815","position":1,"is_corresponding":false},{"id":1393665,"name":"Thy Pham","orcid":"0000-0001-5281-9147","position":2,"is_corresponding":false},{"id":59206,"name":"David P. Bartel","orcid":"0000-0002-3872-2856","position":3,"is_corresponding":false},{"id":1393664,"name":"Mona L. Hall","orcid":"0000-0001-8509-6838","position":0,"is_corresponding":true}],"reference_count":55,"raw_metadata":null,"created_at":"2026-07-19T02:49:54.058858Z","pmid":"41099710","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":[]}