G-quadruplex DNA drives genomic instability and represents a targetable molecular abnormality in ATRX-deficient malignant glioma

• Published in: Nature communications Vol. 10; no. 1; p. 943
• Main Authors: Wang, Yuxiang, Yang, Jie, Wild, Aaron T., Wu, Wei H., Shah, Rachna, Danussi, Carla, Riggins, Gregory J., Kannan, Kasthuri, Sulman, Erik P., Chan, Timothy A., Huse, Jason T.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 26.02.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 13/31; 14/19; 14/32; 38/35; 45/15; 631/208; 631/337; 631/67; 64/60; 692/4017; 692/4028; Animals; Brain Neoplasms - genetics; Brain Neoplasms - metabolism; Cell death; Cell Line, Tumor; Copy number; Deactivation; Deoxyribonucleic acid; DNA; DNA biosynthesis; DNA Copy Number Variations; DNA Damage; DNA Replication; DNA structure; DNA, Neoplasm - chemistry; DNA, Neoplasm - genetics; DNA, Neoplasm - metabolism; Drug development; G-Quadruplexes; Gene Knockdown Techniques; Genomic Instability; Glioma; Glioma - genetics; Glioma - metabolism; Heterografts; Humanities and Social Sciences; Humans; Inactivation; Ionizing radiation; Mice; Mice, Nude; multidisciplinary; Mutation; Organic chemistry; Protein structure; Radiation damage; Science; Science (multidisciplinary); Secondary structure; Stability; Stabilization; Structural damage; Thalassemia; Therapeutic targets; X-linked Nuclear Protein - deficiency; X-linked Nuclear Protein - genetics
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-08905-8

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. ATRX deficiency is linked to genomic stability in cancer cells. Here, the authors show that ATRX inactivation induces G-quadruplex formation, leading to genome-wide DNA damage, and the use of G-quadruplex stabilisers can be exploited therapeutically in ATRX deficient gliomas.