{"doi":"10.3390/molecules30061264","title":"Structural Insights into the Nonmutagenicity of 2-Haloacetophenone","abstract":"A wide variety of endogenous and exogenous alkylating agents covalently modify DNA to produce N7-alkyl-2′-deoxyguanosine (N7-alkylG) adducts as major DNA lesions. The mutagenic potentials of many N7-alkylG adducts with an intercalatable moiety remain poorly understood. We have discovered that the antiriot agent 2-chloroacetophenone readily reacts with dG to produce N7-acetophenone-dG adducts, implicating the genotoxic properties of 2-chloroacetophenone. 2-Chloroacetophenone, however, has been found to be nonmutagenic in both bacterial and mammalian cells. To gain insights into the nonmutagenic nature of N7-acetophenone-dG, we prepared N7-acetophenone-dG-containing oligonucleotide via 2′-fluorine-mediated transition-state destabilization and conducted kinetic and structural studies of human DNA polymerase eta (polη) incorporating nucleotide opposite 2′-F-N7-acetophenone-dG. The kinetic experiments reveal that the presence of the lesion at the templating position greatly hinders nucleotide incorporation. A crystal structure of polη bound to a nonhydrolyzable dCTP analog opposite 2′-F-N7-acetophenone-dG shows that the templating N7-acetophenone-dG is in a syn conformation, precluding binding of an incoming nucleotide in the catalytic site. These unusual conformations explain the observed inefficient incorporation of nucleotide opposite the lesion. Our studies suggest that certain bulky N7-alkylG lesions adopt a syn conformer and present an intercalatable moiety into the nascent base-pairing site, deterring nucleotide incorporation and thus lowering mutagenicity.","journal":"Molecules","year":2025,"id":551994,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9553,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":377841,"name":"Naveen Kumar Rayala","orcid":null,"position":1,"is_corresponding":false},{"id":1447916,"name":"Ritesh Pal","orcid":"0000-0003-3761-6485","position":2,"is_corresponding":false},{"id":376806,"name":"Seongmin Lee","orcid":"0000-0001-6635-8775","position":3,"is_corresponding":false},{"id":376805,"name":"Hunmin Jung","orcid":"0000-0002-8171-0412","position":0,"is_corresponding":true}],"reference_count":28,"raw_metadata":null,"created_at":"2026-07-19T02:54:29.318076Z","pmid":"40142039","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":[]}