@article{d3af7b3c51d94730aadbfc6378af34d9,
title = "G-quadruplex DNA drives genomic instability and represents a targetable molecular abnormality in ATRX-deficient malignant glioma",
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.",
author = "Yuxiang Wang and Jie Yang and Wild, {Aaron T.} and Wu, {Wei H.} and Rachna Shah and Carla Danussi and Riggins, {Gregory J.} and Kasthuri Kannan and Sulman, {Erik P.} and Chan, {Timothy A.} and Huse, {Jason T.}",
note = "Funding Information: We would like to thank Drs. Peter Lansdorp and Shankar Balasubarmanian for providing the 1H6 and hf2 antibodies, respectively. We would also like to acknowledge Dr. Cameron Brennan for providing the TS 543 GSC line. Finally, we would like to acknowledge the Genomics Core Facility at the Albert Einstein College of Medicine for their assistance in performing SNP arrays, and the Molecular Cytogenetics Core at MSKCC for Tel-FISH. J.T.H. is supported by a Research Scholars Grant, RSG-16-179-01-DMC, from the American Cancer Society. Support for this work also came from the Sontag Foundation (J.T.H.), the Sidney Kimmel Foundation (J.T.H.), and Cycle for Survival (J.T.H.). We acknowledge support from two NIH/NCI Cancer Center Support Grants (CCSGs) for MDACC (P30 CA016672) and MSKCC (P30 CA08748). Funding Information: Competing interests: T.A.C. is a co-founder of Gritstone Oncology and holds equity. He holds equity in An2H. He acknowledges grant funding from Bristol-Myers Squibb, AstraZeneca, Illumina, Pfizer, An2H, and Eisai, and he has served as a paid advisor for Bristol-Myers Squibb, Illumina, Eisai, and An2H. M.S.K. has licensed the use of TMB for the identification of patients that benefit from immune checkpoint therapy to PGDx and T.A.C. receives royalties as part of this licensing agreement. The remaining authors declare no competing interests. Publisher Copyright: {\textcopyright} 2019, The Author(s).",
year = "2019",
month = dec,
day = "1",
doi = "10.1038/s41467-019-08905-8",
language = "English (US)",
volume = "10",
journal = "Nature communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}