TY - JOUR T1 - IDH1<sup>R132H</sup> acts as a tumor suppressor in glioma via epigenetic upregulation of the DNA damage response JF - bioRxiv DO - 10.1101/389817 SP - 389817 AU - Felipe J. Núñez AU - Flor M. Mendez AU - Padma Kadiyala AU - Mahmoud S. Alghamri AU - Masha G. Savelieff AU - Carl Koschmann AU - Anda-Alexandra Calinescu AU - Neha Kamran AU - Rohin Patel AU - Stephen Carney AU - Marissa Z. Guo AU - Maria B. Garcia-Fabiani AU - Santiago Haase AU - Marta Edwards AU - Mats Ljungman AU - Tingting Qin AU - Maureen A. Sartor AU - Rebecca Tagett AU - Sriram Venneti AU - Jacqueline Brosnan-Cashman AU - Alan Meeker AU - Vera Gorbunova AU - Lili Zhao AU - Daniel M. Kremer AU - Li Zhang AU - Costas A. Lyssiotis AU - Lindsey Jones AU - Cameron J. Herting AU - James L. Ross AU - Dolores Hambardzumyan AU - Shawn Hervey-Jumper AU - Maria E. Figueroa AU - Pedro R. Lowenstein AU - Maria G. Castro Y1 - 2018/01/01 UR - http://biorxiv.org/content/early/2018/08/10/389817.abstract N2 - One sentence summary Mutant IDH1 acts as a tumor suppressor when co-expressed together with TP53 and ATRX inactivating mutations in glioma, inducing genomic stability, DNA repair and resistance to genotoxic therapies.Abstract Glioma patients whose tumors carry a mutation in the Isocitrate Dehydrogenase 1 (IDH1R132H) gene are younger at the time of diagnosis and survive longer. The molecular glioma subtype which we modelled, harbors IDH1R132H, tumor protein 53 (TP53) and alpha-thalassemia/mental retardation syndrome X-linked (ATRX) loss. The impact of IDH1R132H on genomic stability, DNA damage response (DDR) and DNA repair in this molecular glioma subtype is unknown. We discovered that IDH1R132H expression in the genetic context of ATRX and TP53 inactivation: (i) increases median survival (MS), (ii) enhances DDR activity via epigenetic upregulation of Ataxia-telangiectasia mutated (ATM) signaling, and (iii) elicits tumor radioresistance. Pharmacological inhibition of ATM or checkpoint kinase 1 and 2 (CHK1/2), two essential kinases in the DDR pathways, restored tumors’ radiosensitivity. Translation of these findings for mlDH1 glioma patients could significantly improve the therapeutic efficacy of radiotherapy, and thus have a major impact on patient survival. ER -