{"doi":"10.15252/embj.2022113360","title":"A non‐proteolytic release mechanism for HMCES‐DNA‐protein crosslinks","abstract":"The conserved protein HMCES crosslinks to abasic (AP) sites in ssDNA to prevent strand scission and the formation of toxic dsDNA breaks during replication. Here, we report a non-proteolytic release mechanism for HMCES-DNA-protein crosslinks (DPCs), which is regulated by DNA context. In ssDNA and at ssDNA-dsDNA junctions, HMCES-DPCs are stable, which efficiently protects AP sites against spontaneous incisions or cleavage by APE1 endonuclease. In contrast, HMCES-DPCs are released in dsDNA, allowing APE1 to initiate downstream repair. Mechanistically, we show that release is governed by two components. First, a conserved glutamate residue, within HMCES' active site, catalyses reversal of the crosslink. Second, affinity to the underlying DNA structure determines whether HMCES re-crosslinks or dissociates. Our study reveals that the protective role of HMCES-DPCs involves their controlled release upon bypass by replication forks, which restricts DPC formation to a necessary minimum.","journal":"The EMBO Journal","year":2023,"id":332423,"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":25,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9485,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":989992,"name":"Sophie Dürauer","orcid":null,"position":1,"is_corresponding":false},{"id":989994,"name":"Florian Grünert","orcid":null,"position":2,"is_corresponding":false},{"id":1058593,"name":"Kha The Nguyen","orcid":"0000-0001-9191-8754","position":3,"is_corresponding":false},{"id":1058594,"name":"Richa Nigam","orcid":"0009-0004-3243-2489","position":4,"is_corresponding":false},{"id":989995,"name":"Denitsa Yaneva","orcid":null,"position":5,"is_corresponding":false},{"id":1030382,"name":"Pedro Weickert","orcid":null,"position":6,"is_corresponding":false},{"id":503230,"name":"Rachel Bezalel‐Buch","orcid":"0000-0002-8798-3649","position":7,"is_corresponding":false},{"id":989552,"name":"Daniel R. Semlow","orcid":"0000-0001-6538-9713","position":8,"is_corresponding":false},{"id":989553,"name":"Julian Stingele","orcid":"0000-0001-6020-2075","position":9,"is_corresponding":false},{"id":989991,"name":"Maximilian Donsbach","orcid":null,"position":0,"is_corresponding":true}],"reference_count":41,"raw_metadata":null,"created_at":"2026-07-19T01:09:30.139849Z","pmid":"37519246","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":[]}