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

Yuxiang Wang,Wei H Wu,Kasthuri Kannan,Timothy A Chan,Jie Yang,Rachna Shah,Gregory J Riggins,Aaron T Wild,Jason T Huse,Carla Danussi,Erik P Sulman

doi:10.1038/s41467-019-08905-8

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.

Highlights

Mutational inactivation of ATRX (α-thalassemia mental retardation X-linked) represents a defining molecular alteration in large subsets of malignant glioma
ATRX loss has been implicated in alternative lengthening of telomeres (ALT), an abnormal telomerase-independent mechanism of telomere maintenance based on homologous recombination[16,17]
We found that CX-3543 treatment potentiated the cytotoxicity of both ionizing radiation (IR) and HU, and while these effects were significant for both normal human astrocyte (NHA) genotypes, they were strong in the setting of ATRX deficiency (Fig. 6e, f)

Summary

Introduction

Mutational inactivation of ATRX (α-thalassemia mental retardation X-linked) represents a defining molecular alteration in large subsets of malignant glioma. ATRX deficiency has been repeatedly linked to replication stress, DNA damage, copy number alterations (CNAs), and aneuploidy[18,19,20,21,22,23], and recent work has associated ATRX deficiency with copy number loss at ribosomal DNA loci[24] Whether and how such genomic instability contributes to the initiation and/or evolution of malignant glioma remains unclear. G4 stabilization in ATRX-deficient NHAs and GSCs effectively synergized with other DNA-damaging treatment strategies, including ionizing radiation These findings clarify distinct mechanisms by which G4s influence ATRX-deficient glioma pathogenesis and indicate that G4 stabilization may represent an attractive therapeutic strategy for the selective targeting of ATRX-mutant cancers

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Conclusion