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The role of TFs in regulating these processes in cancers remains unclear. Here, it is shown that oncogenetic ETS transcription factor ETV4 controls DNA replication through both transcriptional and non\u2010transcriptional mechanisms in non\u2010small cell lung cancer (NSCLC). ETV4 localizes to specific DNA replication origins and interacts with the origin recognition complex subunits ORC1 and ORC6 during the G1\/S phase, facilitating origin formation. Using quantitative in situ analysis of protein interactions at DNA replication forks (SIRF) assays, it is shown that ETV4 transiently localizes to replication forks in the S phase. It interacts with replicative helicase MCM2 N\u2010terminal, histone H3, and histone\u2010chaperone FACT and is involved in histone processing during replication. Additionally, ETV4 transcriptionally regulates key replisome genes MCM2, MCM4, MCM5, MCM10, and ORC1, influencing their expression and recruitment to chromatin. Due to its binding at the origin\u2010promoter locus like the MCM4 gene, ETV4 overexpression increases R\u2010loop formation, DNA damage, and cell death under external replication stress induced by topoisomerase I (TOP1) inhibitor. These findings highlight the dual role of ETV4 in replication and transcription and suggest that targeting TOP1 could be a synthetic\u2010lethal approach in ETV4\u2010overexpressed lung cancer.<\/jats:p>","DOI":"10.1002\/advs.202409307","type":"journal-article","created":{"date-parts":[[2025,6,23]],"date-time":"2025-06-23T09:55:55Z","timestamp":1750672555000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Topoisomerase I Inhibition in ETV4\u2010overexpressed Non\u2010Small Cell Lung Cancer Promotes Replication and Transcription Mediated R\u2010Loop Accumulation and DNA Damage"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8099-2366","authenticated-orcid":false,"given":"Jiaxi","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Pathology Hebei Medical University Center of Metabolic Diseases and Cancer Research Institute of Medical and Health Science Hebei Medical University  Shijiazhuang 050017 P. 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