{"doi":"10.1101/2022.12.18.520715","title":"An auto-release mechanism for HMCES-DNA-protein crosslinks","abstract":"Summary 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 and cleavage by APE1 endonuclease. In contrast, HMCES-DPCs are quickly 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":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":299655,"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":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9467,"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":989992,"name":"Sophie Dürauer","orcid":null,"position":1,"is_corresponding":false},{"id":989993,"name":"Kha T. Nguyen","orcid":null,"position":2,"is_corresponding":false},{"id":989994,"name":"Florian Grünert","orcid":null,"position":3,"is_corresponding":false},{"id":989995,"name":"Denitsa Yaneva","orcid":null,"position":4,"is_corresponding":false},{"id":989552,"name":"Daniel R. Semlow","orcid":"0000-0001-6538-9713","position":5,"is_corresponding":false},{"id":989553,"name":"Julian Stingele","orcid":"0000-0001-6020-2075","position":6,"is_corresponding":false},{"id":989991,"name":"Maximilian Donsbach","orcid":null,"position":0,"is_corresponding":true}],"reference_count":39,"raw_metadata":null,"created_at":"2026-07-19T00:31:44.904250Z","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":[]}