{"doi":"10.1016/j.celrep.2022.110369","title":"DOT1L activity in leukemia cells requires interaction with ubiquitylated H2B that promotes productive nucleosome binding","abstract":"DOT1L methylates histone H3 lysine 79 during transcriptional elongation and is stimulated by ubiquitylation of histone H2B lysine 120 (H2BK120ub) in a classical trans-histone crosstalk pathway. Aberrant genomic localization of DOT1L is implicated in mixed lineage leukemia (MLL)-rearranged leukemias, an aggressive subset of leukemias that lacks effective targeted treatments. Despite recent atomic structures of DOT1L in complex with H2BK120ub nucleosomes, fundamental questions remain as to how DOT1L-ubiquitin and DOT1L-nucleosome acidic patch interactions observed in these structures contribute to nucleosome binding and methylation by DOT1L. Here, we combine bulk and single-molecule biophysical measurements with cancer cell biology to show that ubiquitin and cofactor binding drive conformational changes to stimulate DOT1L activity. Using structure-guided mutations, we demonstrate that ubiquitin and nucleosome acidic patch binding by DOT1L are required for cell proliferation in the MV4; 11 leukemia model, providing proof of principle for MLL targeted therapeutic strategies.","journal":"Cell Reports","year":2022,"id":251649,"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":24,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9546,"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":895070,"name":"Satya P. Yadav","orcid":"0000-0001-6646-7787","position":1,"is_corresponding":false},{"id":655397,"name":"Dongxu Li","orcid":"0000-0003-1440-7293","position":2,"is_corresponding":false},{"id":895071,"name":"Carinne N. Geil","orcid":"0000-0003-3532-9853","position":3,"is_corresponding":false},{"id":895072,"name":"C. B. Smith","orcid":"0000-0002-3092-0807","position":4,"is_corresponding":false},{"id":247178,"name":"Gang Greg Wang","orcid":"0000-0002-7210-9940","position":5,"is_corresponding":false},{"id":44963,"name":"Tae-Hee Lee","orcid":"0000-0003-2034-6394","position":6,"is_corresponding":false},{"id":266826,"name":"Robert K. McGinty","orcid":"0000-0001-9641-7350","position":7,"is_corresponding":false},{"id":266823,"name":"Cathy J. Spangler","orcid":"0000-0003-2334-3957","position":0,"is_corresponding":true}],"reference_count":44,"raw_metadata":null,"created_at":"2026-07-19T00:24:41.993282Z","pmid":"35172132","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":[]}