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, Jason T. Huse

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number943
JournalNature communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

Fingerprint

G-Quadruplexes
Genomic Instability
abnormalities
Glioma
deoxyribonucleic acid
DNA Damage
DNA
X-Linked Mental Retardation
Thalassemia
Stabilization
stabilization
Ionizing Radiation
damage
Genetic Therapy
Ionizing radiation
Cell Death
Cell death
death
ionizing radiation
deactivation

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

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

In: Nature communications, Vol. 10, No. 1, 943, 01.12.2019.

Research output: Contribution to journalArticle

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. / G-quadruplex DNA drives genomic instability and represents a targetable molecular abnormality in ATRX-deficient malignant glioma. In: Nature communications. 2019 ; Vol. 10, No. 1.
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AU - Shah, Rachna

AU - Danussi, Carla

AU - Riggins, Gregory J

AU - Kannan, Kasthuri

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