{"doi":"10.1101/2021.06.07.447350","title":"Bidirectional cooperation between Ubtf1 and SL1 determines RNA Polymerase I promoter recognition <i>in cell</i> and is negatively affected in the UBTF-E210K neuroregression syndrome","abstract":"ABSTRACT Transcription of the ∼200 mouse and human ribosomal RNA genes (rDNA) by RNA Polymerase I (RPI/PolR1) accounts for 80% of total cellular RNA, around 35% of all nuclear RNA synthesis, and determines the cytoplasmic ribosome complement. It is therefore a major factor controlling cell growth and its misfunction has been implicated in hypertrophic and developmental disorders. Activation of each rDNA repeat requires nucleosome replacement by the architectural multi-HMGbox factor UBTF to create a 15kbp nucleosome free region (NFR). Formation of this NFR is also essential for recruitment of the TBP-TAF I factor SL1 and for preinitiation complex (PIC) formation at the gene and enhancer-associated promoters of the rDNA. However, these promoters show little sequence commonality and neither UBTF nor SL1 display significant DNA sequence binding specificity, making what drives PIC formation a mystery. Here we show that cooperation between SL1 and the longer UBTF1 splice variant generates the specificity required for rDNA promoter recognition in cell . We find that conditional deletion of the Taf1b subunit of SL1 causes a striking depletion UBTF at both rDNA promoters but not elsewhere across the rDNA. We also find that while both UBTF1 and −2 variants bind throughout the rDNA NFR, only UBTF1 is present with SL1 at the promoters. The data strongly suggest an induced-fit model of RPI promoter recognition in which UBTF1 plays an architectural role. Interestingly, a recurrent UBTF-E210K mutation and the cause of a pediatric neurodegeneration syndrome provides indirect support for this model. E210K knock-in cells show enhanced levels of the UBTF1 splice variant and a concomitant increase in active rDNA copies. In contrast, they also display reduced rDNA transcription and promoter recruitment of SL1. We suggest the underlying cause of the UBTF-E210K syndrome is therefore a reduction in cooperative UBTF1-SL1 promoter recruitment that may be partially compensated by enhanced rDNA activation.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":218894,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9637,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":817025,"name":"Dany S. Sibai","orcid":"0000-0001-8417-1111","position":1,"is_corresponding":false},{"id":817026,"name":"Mélissa Valere","orcid":"0000-0002-8704-3809","position":2,"is_corresponding":false},{"id":674205,"name":"Jean-Clément Mars","orcid":"0000-0001-8904-9502","position":3,"is_corresponding":false},{"id":817027,"name":"Frédéric Lessard","orcid":"0000-0002-1724-7267","position":4,"is_corresponding":false},{"id":470345,"name":"Roderick Hori","orcid":null,"position":5,"is_corresponding":false},{"id":336024,"name":"Mohammad Moshahid Khan","orcid":"0000-0003-4679-294X","position":6,"is_corresponding":false},{"id":817480,"name":"Victor Y. Stefanovsky","orcid":null,"position":7,"is_corresponding":false},{"id":447465,"name":"Mark S. LeDoux","orcid":"0000-0002-1748-3390","position":8,"is_corresponding":false},{"id":817028,"name":"Tom Moss","orcid":"0000-0003-2047-4783","position":9,"is_corresponding":false},{"id":817024,"name":"Michel G. Tremblay","orcid":"0000-0003-2545-3682","position":0,"is_corresponding":true}],"reference_count":53,"raw_metadata":null,"created_at":"2026-07-18T23:53:33.915158Z","pmid":null,"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":[]}