TY - JOUR T1 - G-quadruplex DNA drives genomic instability and represents a targetable molecular abnormality in ATRX-deficient malignant glioma JF - bioRxiv DO - 10.1101/347542 SP - 347542 AU - Yuxiang Wang AU - Jie Yang AU - Wei Wu AU - Rachna Shah AU - Carla Danussi AU - Gregory J. Riggins AU - Kasthuri Kannan AU - Erik P. Sulman AU - Timothy A. Chan AU - Jason T. Huse Y1 - 2018/01/01 UR - http://biorxiv.org/content/early/2018/06/14/347542.abstract N2 - Mutational inactivation of ATRX (α-thalassemia mental retardation X-linked) represents a defining molecular alteration in large subsets of malignant glioma. Yet the pathogenic consequences of ATRX deficiency remain unclear, as do tractable mechanisms for its therapeutic targeting. Here we report that ATRX loss in isogenic glioma model systems induces replication stress and DNA damage by way of G-quadruplex (G4) DNA secondary structure. Moreover, these effects are associated with the acquisition of disease-relevant copy number alterations over time. We then demonstrate, both in vitro and in vivo, that ATRX deficiency selectively enhances DNA damage and cell death following chemical G4 stabilization. Finally, we show that G4 stabilization synergizes with other DNA-damaging therapies, including ionizing radiation, in the ATRX-deficient context. Our findings reveal novel pathogenic mechanisms driven by ATRX deficiency in glioma, while also pointing to tangible strategies for drug development. ER -