{"doi":"10.1101/2021.09.24.461537","title":"A <i>Drosophila Su(H)</i> Model of Adams-Oliver Syndrome Reveals Notch Cofactor Titration as a Mechanism Underlying Developmental Defects","abstract":"ABSTRACT Notch signaling is a conserved pathway that converts extracellular receptor-ligand interactions into changes in gene expression via a single transcription factor (CBF1/RBPJ in mammals; Su(H) in Drosophila ). In humans, RBPJ variants have been linked to Adams-Oliver syndrome (AOS), a rare autosomal dominant disorder characterized by scalp, cranium, and limb defects. Here, we found that a previously described Drosophila Su(H) allele encodes a missense mutation that alters an analogous residue found in an AOS-associated RBPJ variant. Importantly, genetic studies support a model that Drosophila with a single copy of the AOS-like Su(H) allele behave in an opposing manner as flies with a Su(H) null allele due to a dominant activity of sequestering either the Notch co-activator or the antagonistic Hairless co-repressor. Consistent with this model, AOS-like Su(H) and Rbpj variants decrease DNA binding activity compared to wild type proteins, but these variants do not significantly alter protein binding to the Notch co-activator or the fly and mammalian co-repressors, respectively. Taken together, these data suggest a cofactor sequestration mechanism underlies AOS phenotypes associated with RBPJ variants, whereby a single RBPJ allele encodes a protein with compromised DNA binding activity that retains cofactor binding, resulting in Notch target gene dysregulation.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":226804,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9522,"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":582727,"name":"Lisa M. Gutzwiller","orcid":"0000-0001-8583-8328","position":1,"is_corresponding":false},{"id":340131,"name":"Yi Kuang","orcid":"0000-0002-1509-3620","position":2,"is_corresponding":false},{"id":281131,"name":"Yoshinobu Odaka","orcid":"0000-0003-3966-5475","position":3,"is_corresponding":false},{"id":830654,"name":"Phillipp Hoffmeister","orcid":null,"position":4,"is_corresponding":false},{"id":830655,"name":"Stefanie Hauff","orcid":null,"position":5,"is_corresponding":false},{"id":713333,"name":"Aleksandra Turkiewicz","orcid":"0000-0002-4386-1180","position":6,"is_corresponding":false},{"id":55490,"name":"Emily Harding‐Theobald","orcid":"0000-0003-0810-8596","position":7,"is_corresponding":false},{"id":830152,"name":"Patrick J. Dolph","orcid":"0000-0001-9770-727X","position":8,"is_corresponding":false},{"id":687142,"name":"Tilman Borggrefe","orcid":null,"position":9,"is_corresponding":false},{"id":658534,"name":"Franz Oswald","orcid":"0000-0002-2923-5765","position":10,"is_corresponding":false},{"id":340132,"name":"Brian Gebelein","orcid":"0000-0001-9791-9061","position":11,"is_corresponding":false},{"id":340130,"name":"Rhett A. Kovall","orcid":"0000-0003-0520-1613","position":12,"is_corresponding":false},{"id":582729,"name":"Ellen K. Gagliani","orcid":"0000-0001-7270-6254","position":0,"is_corresponding":true}],"reference_count":41,"raw_metadata":null,"created_at":"2026-07-18T23:54:38.004707Z","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":[]}