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Top2 adduct removal requires endonuclease activity prior to repair of the resulting DNA double-strand break (DSB). We show that the non-homologous end joining (NHEJ) enzyme Artemis is a key player in the process and a major target for treatment of human B-cell acute lymphoblastic leukemia (ALL). An Artemis knockout is sensitive to etoposide treatment at nanomolar levels and has significantly more unrepaired DNA DSBs. Inhibition of the Artemis activator, DNA-dependent Protein Kinase Catalytic Subunit (DNA-PKcs), acts synergistically with Top2 poisons to further sensitize ALL cells. Genetic loss of Artemis ablates this synergy underscoring its critical role in this drug interaction. Furthermore, Artemis loss results in a significant accumulation of covalent Top2A DNA adducts following etoposide treatment and a significant increase in unrepaired DNA DSBs. As clinical data demonstrate that high Artemis expression correlates with poor survival in several cancers, our work may unlock new avenues for the treatment of aggressive cancers.<\/jats:p>","DOI":"10.1038\/s42003-026-10731-w","type":"journal-article","created":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T12:04:10Z","timestamp":1787313850000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting Artemis sensitizes acute lymphoblastic leukemia cells to topoisomerase 2 poisons by disrupting DNA-PKcs-dependent repair"],"prefix":"10.1038","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-9657-6146","authenticated-orcid":false,"given":"Melissa L.","family":"Folkerts","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cameron","family":"Hom","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9200-3510","authenticated-orcid":false,"given":"Angie T. 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