{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T05:06:17Z","timestamp":1789189577257,"version":"build-2803163510"},"reference-count":58,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T00:00:00Z","timestamp":1788998400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000054","name":"NIH\/NCI K01","doi-asserted-by":"publisher","award":["CA226346"],"award-info":[{"award-number":["CA226346"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"name":"NIH","award":["CA264983"],"award-info":[{"award-number":["CA264983"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Glioblastoma (GBM) standard of care includes surgical resection followed by ionizing radiation (IR) and Temozolomide, which induce DNA double-strand breaks. Homologous recombination (HR), a critical DNA double-strand break repair pathway, is augmented in GBM, contributing to resistance and poor patient outcomes. Here, we demonstrate that increasing deoxyribonucleoside triphosphate (dNTP) levels impairs HR-mediated double-strand break repair, rendering GBM cells sensitive to IR and Temozolomide. Interestingly, combining an elevated dNTP pool level with IR and\/or Temozolomide promotes the recruitment of DNA polymerase-\u03b1\/primase, which is typically involved in Okazaki fragment synthesis during DNA replication, to the DNA double-strand break site, thereby interfering with DNA end resection. Specifically, higher dNTP pool levels disrupted the recruitment of HR-associated proteins such as RPA70 and RAD51, an effect reversed by Aphidicolin, a DNA polymerase-\u03b1\/primase inhibitor. Impaired HR delayed IR- and\/or Temozolomide-induced DNA double-strand break repair, leading to growth arrest and apoptosis. Furthermore, higher dNTP pool levels led to downregulation of DNA replication and HR-associated genes, while upregulating several pro-apoptotic genes. Increased sensitivity to IR and Temozolomide was also observed in engineered IR-resistant GBM cell lines and in naturally recurrent patient-derived GBM cells that emerge post-therapy. These findings emphasize how dNTP pool levels regulate HR and uncover a promising vulnerability that could be exploited to overcome resistance to DNA-damaging treatments in GBM and beyond.<\/jats:p>","DOI":"10.3390\/ijms27188045","type":"journal-article","created":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T09:13:03Z","timestamp":1789031583000},"page":"8045","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Elevated dNTP Pool Levels Impair Homologous Recombination and Enhance Glioblastoma Sensitivity to Irradiation and Temozolomide"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5714-2518","authenticated-orcid":false,"given":"Dominique","family":"Monroe","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA"},{"name":"Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9936-1671","authenticated-orcid":false,"given":"Mercy","family":"Kehinde-Ige","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA"},{"name":"Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA"},{"name":"Immunology Center of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arilyn","family":"Williams","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA"},{"name":"Georgia Cancer Center, Augusta University, Augusta, GA 30912, 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USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramsha","family":"Khanam","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA"},{"name":"Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aman","family":"Kalsi","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA"},{"name":"Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2902-3671","authenticated-orcid":false,"given":"Ali S.","family":"Arbab","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA"},{"name":"Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5831-7022","authenticated-orcid":false,"given":"Daitoku","family":"Sakamuro","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA"},{"name":"Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1137-3390","authenticated-orcid":false,"given":"Huidong","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA"},{"name":"Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA"},{"name":"Immunology Center of Georgia, Augusta University, Augusta, GA 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