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

   

Authors:	Wang, Y.; Yang, J.; Wild, A. T.; Wu, W. H.; Shah, R.; Danussi, C.; Riggins, G. J.; Kannan, K.; Sulman, E. P.; Chan, T. A.; Huse, J. T.
Article 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. © 2019, The Author(s).
Journal Title:	Nature Communications
Volume:	10
ISSN:	2041-1723
Publisher:	Nature Publishing Group
Date Published:	2019-02-26
Start Page:	943
Language:	English
DOI:	10.1038/s41467-019-08905-8
PUBMED:	30808951
PROVIDER:	scopus
PMCID:	PMC6391399
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85062148383&doi=10.1038%2fs41467-019-08905-8&partnerID=40&md5=57539a2619d2a2f2fe539eefc8f93887
Notes:	Article -- Export Date: 1 April 2019 -- Source: Scopus

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