{"doi":"10.1093/nar/gkae845","title":"<i>N</i> 2-Alkyl-dG lesions elicit R-loop accumulation in the genome","abstract":"Humans are exposed to DNA alkylating agents through endogenous metabolism, environmental exposure and cancer chemotherapy. The resulting alkylated DNA adducts may elicit genome instability by perturbing DNA replication and transcription. R-loops regulate various cellular processes, including transcription, DNA repair, and telomere maintenance. However, unscheduled R-loops are also recognized as potential sources of DNA damage and genome instability. In this study, by employing fluorescence microscopy and R-loop sequencing approaches, we uncovered, for the first time, that minor-groove N2-alkyl-dG lesions elicit elevated R-loop accumulation in chromatin and in plasmid DNA in cells. We also demonstrated that the N2-alkyl-dG-induced R-loops impede transcription elongation and compromise genome integrity. Moreover, genetic depletion of DDX23, a R-loop helicase, renders cells more sensitive toward benzo[a]pyrene diolepoxide, a carcinogen that induces mainly the minor-groove N2-dG adduct. Together, our work unveiled that unrepaired minor-groove N2-alkyl-dG lesions may perturb genome integrity through augmenting R-loop levels in chromatin. Our findings suggest a potential therapeutic strategy involving the combination of R-loop helicase inhibitors with DNA alkylating drugs.","journal":"Nucleic Acids Research","year":2024,"id":447597,"datarank":0.3031069100879498,"base_score":1.9459101490553132,"endowment":1.9459101490553132,"self_citation_contribution":0.29188652235829704,"citation_network_contribution":0.011220387729652762,"self_endowment_contribution":0.29188652235829704,"citer_contribution":0.011220387729652762,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":6,"citers_with_citation_signal":2,"citers_with_endowment":2,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.946,"is_data_producer":true,"deposit_databanks":{"GEO":["GSE 248210"]},"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":930575,"name":"Feng Tang","orcid":"0000-0001-9748-3712","position":1,"is_corresponding":false},{"id":1260885,"name":"Ting Zhao","orcid":"0000-0002-9921-3692","position":2,"is_corresponding":false},{"id":269778,"name":"Jun Yuan","orcid":"0000-0002-8265-0239","position":4,"is_corresponding":false},{"id":404557,"name":"Andrew H. Kellum","orcid":"0000-0003-4178-8175","position":5,"is_corresponding":false},{"id":110450,"name":"Yinsheng Wang","orcid":"0000-0001-5565-283X","position":6,"is_corresponding":false},{"id":704489,"name":"Yinan Wang","orcid":"0000-0001-8030-9494","position":0,"is_corresponding":true}],"reference_count":51,"raw_metadata":null,"created_at":"2026-07-19T02:02:03.354708Z","pmid":"39351875","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":[]}