{"doi":"10.1093/nar/gkaa520","title":"Alternative splicing and allosteric regulation modulate the chromatin binding of UHRF1","abstract":"UHRF1 is an important epigenetic regulator associated with apoptosis and tumour development. It is a multidomain protein that integrates readout of different histone modification states and DNA methylation with enzymatic histone ubiquitylation activity. Emerging evidence indicates that the chromatin-binding and enzymatic modules of UHRF1 do not act in isolation but interplay in a coordinated and regulated manner. Here, we compared two splicing variants (V1, V2) of murine UHRF1 (mUHRF1) with human UHRF1 (hUHRF1). We show that insertion of nine amino acids in a linker region connecting the different TTD and PHD histone modification-binding domains causes distinct H3K9me3-binding behaviour of mUHRF1 V1. Structural analysis suggests that in mUHRF1 V1, in contrast to V2 and hUHRF1, the linker is anchored in a surface groove of the TTD domain, resulting in creation of a coupled TTD-PHD module. This establishes multivalent, synergistic H3-tail binding causing distinct cellular localization and enhanced H3K9me3-nucleosome ubiquitylation activity. In contrast to hUHRF1, H3K9me3-binding of the murine proteins is not allosterically regulated by phosphatidylinositol 5-phosphate that interacts with a separate less-conserved polybasic linker region of the protein. Our results highlight the importance of flexible linkers in regulating multidomain chromatin binding proteins and point to divergent evolution of their regulation.","journal":"Nucleic Acids Research","year":2020,"id":70497,"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":19,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9542,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":375031,"name":"Sarah Kreuz","orcid":null,"position":1,"is_corresponding":false},{"id":375032,"name":"Alexander Lemak","orcid":null,"position":2,"is_corresponding":false},{"id":373286,"name":"Papita Mandal","orcid":"0000-0003-4398-8971","position":3,"is_corresponding":false},{"id":373287,"name":"Zhadyra Yerkesh","orcid":"0000-0001-7124-1328","position":4,"is_corresponding":false},{"id":52472,"name":"Alaguraj Veluchamy","orcid":"0000-0002-5349-5794","position":5,"is_corresponding":false},{"id":373288,"name":"Bothayna Al-Gashgari","orcid":"0000-0003-1966-3309","position":6,"is_corresponding":false},{"id":373289,"name":"Abrar Aljahani","orcid":"0000-0001-6640-2641","position":7,"is_corresponding":false},{"id":373290,"name":"Lorena V. Cortés-Medina","orcid":"0000-0001-7718-0730","position":8,"is_corresponding":false},{"id":373291,"name":"Dulat M. Azhibek","orcid":"0000-0002-6627-3285","position":9,"is_corresponding":false},{"id":228421,"name":"Lixin Fan","orcid":"0000-0002-9232-9262","position":10,"is_corresponding":false},{"id":375033,"name":"Michelle S. Ong","orcid":null,"position":11,"is_corresponding":false},{"id":373292,"name":"Shili Duan","orcid":"0000-0002-7855-2425","position":12,"is_corresponding":false},{"id":36740,"name":"Scott Houliston","orcid":"0000-0002-0113-0339","position":13,"is_corresponding":false},{"id":84362,"name":"C.H. Arrowsmith","orcid":"0000-0002-4971-3250","position":14,"is_corresponding":false},{"id":373293,"name":"Wolfgang Fischle","orcid":"0000-0002-2335-8932","position":15,"is_corresponding":false},{"id":375030,"name":"Maria Tauber","orcid":null,"position":0,"is_corresponding":true}],"reference_count":74,"raw_metadata":null,"created_at":"2026-07-18T21:43:32.585486Z","pmid":"32609811","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":[]}