{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T04:27:34Z","timestamp":1786508854132,"version":"build-2736575974"},"posted":{"date-parts":[[2026,8,10]]},"group-title":"Cancer Biology","reference-count":43,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T00:00:00Z","timestamp":1786320000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01CA227821"],"award-info":[{"award-number":["R01CA227821"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01CA289485"],"award-info":[{"award-number":["R01CA289485"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["P50CA165962"],"award-info":[{"award-number":["P50CA165962"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Tawingo Fund"},{"name":"Loglio Fund"},{"DOI":"10.13039\/501100008884","name":"Nakatani Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100008884","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/00gc20a07","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Japanese Society of Cancer Therapy and Kobayashi Foundation for Cancer Research"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,8,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Mutations in isocitrate dehydrogenase 1 (\n                  <jats:italic>IDH1<\/jats:italic>\n                  ) drive the early stages of gliomagenesis while simultaneously imposing replication stress that creates targetable vulnerabilities. Using both\n                  <jats:italic>in vitro<\/jats:italic>\n                  and\n                  <jats:italic>in vivo<\/jats:italic>\n                  models, we show that inhibition of poly(ADP-ribose) glycohydrolase (PARG) induces a poly(ADP-ribose) (PAR)-dependent augmentation of radiosensitivity in\n                  <jats:italic>IDH1<\/jats:italic>\n                  -mutant glioma cells. Metabolic repletion of NAD\n                  <jats:sup>+<\/jats:sup>\n                  fails to rescue this effect, indicating that the vulnerability cannot be explained solely by NAD\n                  <jats:sup>+<\/jats:sup>\n                  depletion. Instead, PARG inhibition profoundly alters replication fork progression and S-phase kinetics in\n                  <jats:italic>IDH1<\/jats:italic>\n                  -mutant cells. Mechanistically, ionizing radiation preferentially activates replication fork-associated damage response proteins DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and X-ray repair cross-complementing protein 1 (XRCC1) in\n                  <jats:italic>IDH1<\/jats:italic>\n                  -mutant cells, a response partially reversed by pharmacologic inhibition of mutant\n                  <jats:italic>IDH1<\/jats:italic>\n                  . Importantly, pharmacologic inhibition of DNA-PKcs with AZD7648 during irradiation disrupts fork-associated repair signaling and markedly enhances cytotoxicity in\n                  <jats:italic>IDH1<\/jats:italic>\n                  -mutant glioma models. Together, these findings identify a PAR-dependent replication fork vulnerability that can be therapeutically exploited to selectively enhance radiosensitivity in\n                  <jats:italic>IDH1<\/jats:italic>\n                  -mutant gliomas.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Statement of significance<\/jats:title>\n                  <jats:p>\n                    <jats:italic>IDH<\/jats:italic>\n                    -mutant gliomas harbor intrinsic replication stress yet lack targeted radiosensitization strategies. We identify a PAR-dependent replication fork vulnerability in which disruption amplifies radiation cytotoxicity by deregulating S-phase fork signaling. Pharmacologic DNA-PKcs inhibition exploits this dependency, providing a genotype-selective approach to enhance radiotherapy in\n                    <jats:italic>IDH<\/jats:italic>\n                    -mutant glioma.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.08.08.743634","type":"posted-content","created":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T15:35:17Z","timestamp":1786376117000},"source":"Crossref","is-referenced-by-count":0,"title":["Augmenting Radiation Sensitivity by Targeting PAR-Dependent Replication Fork Vulnerability in\n                  <i>IDH-<\/i>\n                  Mutant Glioma"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1903-1283","authenticated-orcid":false,"given":"Yosuke","family":"Kitagawa","sequence":"first","affiliation":[{"name":"Translational Neuro-Oncology Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA"},{"name":"Department of 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USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroaki","family":"Nagashima","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Kobe University, Graduate School of Medicine, Hyogo, Kobe, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie J.","family":"Miller","sequence":"additional","affiliation":[{"name":"Translational Neuro-Oncology Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA"},{"name":"Pappas Center for Neuro-Oncology, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroaki","family":"Wakimoto","sequence":"additional","affiliation":[{"name":"Translational Neuro-Oncology Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA"},{"name":"Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical 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