{"doi":"10.1021/jacs.3c12890","title":"Stable Interstrand Cross-Links Generated from the Repair of 1,<i>N</i><sup>6</sup>-Ethenoadenine in DNA by α-Ketoglutarate/Fe(II)-Dependent Dioxygenase ALKBH2","abstract":"DNA cross-links severely challenge replication and transcription in cells, promoting senescence and cell death. In this paper, we report a novel type of DNA interstrand cross-link (ICL) produced as a side product during the attempted repair of 1, N 6 -ethenoadenine (εA) by human α-ketoglutarate/Fe(II)-dependent enzyme ALKBH2. This stable/nonreversible ICL was characterized by denaturing polyacrylamide gel electrophoresis analysis and quantified by high-resolution LC–MS in well-matched and mismatched DNA duplexes, yielding 5.7% as the highest level for cross-link formation. The binary lesion is proposed to be generated through covalent bond formation between the epoxide intermediate of εA repair and the exocyclic N 6 -amino group of adenine or the N 4 -amino group of cytosine residues in the complementary strand under physiological conditions. The cross-links occur in diverse sequence contexts, and molecular dynamics simulations rationalize the context specificity of cross-link formation. In addition, the cross-link generated from attempted εA repair was detected in cells by highly sensitive LC–MS techniques, giving biological relevance to the cross-link adducts. Overall, a combination of biochemical, computational, and mass spectrometric methods was used to discover and characterize this new type of stable cross-link both in vitro and in human cells, thereby uniquely demonstrating the existence of a potentially harmful ICL during DNA repair by human ALKBH2.","journal":"Journal of the American Chemical Society","year":2024,"id":457430,"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":5,"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":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1282714,"name":"Nathania A. Takyi","orcid":"0000-0002-6436-9005","position":1,"is_corresponding":false},{"id":695681,"name":"Yun-Chung Hsiao","orcid":"0000-0003-1189-6511","position":2,"is_corresponding":false},{"id":749478,"name":"Qi Tang","orcid":"0000-0002-8913-0519","position":3,"is_corresponding":false},{"id":1139304,"name":"Yi-Tzai Chen","orcid":null,"position":4,"is_corresponding":false},{"id":687693,"name":"Chih‐Wei Liu","orcid":"0000-0002-0823-0252","position":5,"is_corresponding":false},{"id":245657,"name":"Jian Ma","orcid":"0000-0002-4963-304X","position":6,"is_corresponding":false},{"id":786874,"name":"Rui Qi","orcid":"0000-0001-8936-4641","position":7,"is_corresponding":false},{"id":486846,"name":"Ke Bian","orcid":"0000-0002-1268-2382","position":8,"is_corresponding":false},{"id":1111884,"name":"Zhiyuan Peng","orcid":"0000-0002-1302-914X","position":9,"is_corresponding":false},{"id":693988,"name":"John M. Essigmann","orcid":"0000-0002-2196-5691","position":10,"is_corresponding":false},{"id":225653,"name":"Kun Lü","orcid":"0000-0002-8125-2394","position":11,"is_corresponding":false},{"id":440023,"name":"Stacey D. Wetmore","orcid":"0000-0002-5801-3942","position":12,"is_corresponding":false},{"id":440022,"name":"Deyu Li","orcid":"0000-0002-1082-0569","position":13,"is_corresponding":false},{"id":486998,"name":"Jie Wang","orcid":"0000-0001-7870-0646","position":0,"is_corresponding":true}],"reference_count":81,"raw_metadata":null,"created_at":"2026-07-19T02:03:37.136946Z","pmid":"38573229","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":[]}