{"doi":"10.1101/2022.09.27.509717","title":"Loss of the E3 ubiquitin ligases UBR-5 or HECD-1 restores <i>Caenorhabditis elegans</i> development in the absence of SWI/SNF function","abstract":"Abstract SWItch/Sucrose Non-Fermenting (SWI/SNF) complexes are a family of chromatin remodellers that are conserved across eukaryotes. Mutations in subunits of SWI/SNF cause a multitude of different developmental disorders in humans, most of which have no current treatment options. Here we identify an alanine to valine causing mutation in the SWI/SNF subunit snfc-5 ( SMARCB1 in humans) that prevents embryonic lethality in C. elegans nematodes harbouring a loss-of-function mutation in the SWI/SNF subunit swsn-1 ( SMARCC1/2 in humans). Furthermore, we found that the combination of this specific mutation in snfc-5 and a loss-of-function mutation in either of the E3 ubiquitin ligases ubr-5 ( UBR5 in humans) or hecd-1 ( HECTD1 in humans) can restore development to adulthood in swsn-1 loss-of-function mutants that otherwise die as embryos. Using these mutant models, we established a set of 335 genes that are dysregulated in SWI/SNF mutants that arrest their development embryonically but exhibit near wild-type levels of expression in the presence of suppressor mutations that prevent embryonic lethality, suggesting that SWI/SNF promotes development by regulating this specific subset of genes. In addition, we show that SWI/SNF protein levels are reduced in swsn-1; snfc-5 double mutants and partly restored to wild-type levels in swsn-1; snfc-5; ubr-5 triple mutants, consistent with a model in which UBR-5 regulates SWI/SNF levels by tagging the complex for proteasomal degradation. Our findings establish a link between two E3 ubiquitin ligases and SWI/SNF function and suggest that UBR5 and HECTD1 might be viable therapeutic targets for the many developmental disorders caused by missense mutations in SWI/SNF subunits.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":311634,"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":0.9582,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1008186,"name":"Francesca Conte","orcid":"0000-0003-0842-9314","position":1,"is_corresponding":false},{"id":759686,"name":"Subhanita Ghosh","orcid":"0000-0002-7919-1043","position":2,"is_corresponding":false},{"id":819930,"name":"Yutong Xiao","orcid":"0000-0001-7279-3423","position":3,"is_corresponding":false},{"id":304352,"name":"Jonathan Price","orcid":"0000-0001-6554-5667","position":4,"is_corresponding":false},{"id":1008187,"name":"David Jordan","orcid":"0000-0002-3506-5440","position":5,"is_corresponding":false},{"id":308284,"name":"David Q. Matus","orcid":"0000-0002-1570-5025","position":6,"is_corresponding":false},{"id":605476,"name":"Peter Sarkies","orcid":"0000-0003-0279-6199","position":7,"is_corresponding":false},{"id":1008188,"name":"Petra Beli","orcid":"0000-0001-9507-9820","position":8,"is_corresponding":false},{"id":304354,"name":"Eric A. Miska","orcid":"0000-0002-4450-576X","position":9,"is_corresponding":false},{"id":304349,"name":"Nick Burton","orcid":"0000-0002-5495-3988","position":10,"is_corresponding":false},{"id":1008185,"name":"Lisa Lampersberger","orcid":"0000-0002-3471-9908","position":0,"is_corresponding":true}],"reference_count":56,"raw_metadata":null,"created_at":"2026-07-19T00:33:32.327694Z","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":[]}