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

Yuxiang Wang, Jie Yang, Aaron T. Wild, Wei H. Wu, Rachna Shah, Carla Danussi, Gregory J. Riggins, Kasthuri Kannan, Erik P. Sulman, Timothy A. Chan and Jason T. Huse ()
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Yuxiang Wang: Memorial Sloan-Kettering Cancer Center
Jie Yang: University of Texas MD Anderson Cancer Center
Aaron T. Wild: Memorial Sloan-Kettering Cancer Center
Wei H. Wu: Memorial Sloan-Kettering Cancer Center
Rachna Shah: Memorial Sloan-Kettering Cancer Center
Carla Danussi: University of Texas MD Anderson Cancer Center
Gregory J. Riggins: Johns Hopkins School of Medicine
Kasthuri Kannan: New York University School of Medicine
Erik P. Sulman: University of Texas MD Anderson Cancer Center
Timothy A. Chan: Memorial Sloan-Kettering Cancer Center
Jason T. Huse: University of Texas MD Anderson Cancer Center

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-08905-8

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