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G4s are enzymatically resolved by specialized helicases. Previous in vitro studies showed that DEAH-box helicase 36 (DHX36\/G4R1\/RHAU) has the highest specificity and affinity for G4 structures. Here, by mapping genome-wide DNA double-strand breaks (DSBs), we demonstrate that knockout\u00a0of DHX36 helicase increases DSB enrichment at G4 sites and that the presence of the G4 motif is a significant mediator of genome instability at regulatory regions. The loss of DHX36 corresponds with the significant upregulation of NF-\u03baB transcriptional programs, culminating in the production and secretion of proinflammatory cytokines. Loss of DHX36 expression results in the accumulation of cytoplasmic DNA fragments, an increase in the innate immune signaling stimulator of interferon response cGAMP interactor 1 (STING1) expression, and activation of genes involved in immune response pathways. Importantly, higher levels of DHX36 messenger RNA expression in human B-cell acute lymphoblastic leukemia correlate with improved overall survival relative to lower expression of DHX36, highlighting its critical role in preserving genome integrity at a cellular level and in the context of cancer.<\/jats:p>","DOI":"10.1093\/nar\/gkaf621","type":"journal-article","created":{"date-parts":[[2025,6,14]],"date-time":"2025-06-14T07:44:44Z","timestamp":1749887084000},"source":"Crossref","is-referenced-by-count":12,"title":["Loss of DHX36\/G4R1, a G4 resolvase, drives genome instability and regulates innate immune gene expression in cancer cells"],"prefix":"10.1093","volume":"53","author":[{"given":"Anna R","family":"Bartosik","sequence":"first","affiliation":[{"name":"University of Virginia School of Medicine Department of Biochemistry and Molecular Genetics, , Charlottesville , VA 22908-0733 ,","place":["United 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