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G-quadruplex DNA drives genomic instability and represents a targetable molecular abnormality in ATRX-deficient malignant glioma.
Nature Communications ( IF 14.7 ) Pub Date : 2019-02-26 , DOI: 10.1038/s41467-019-08905-8
Yuxiang Wang 1 , Jie Yang 2 , Aaron T Wild 1 , Wei H Wu 1 , Rachna Shah 1 , Carla Danussi 3 , Gregory J Riggins 4 , Kasthuri Kannan 5 , Erik P Sulman 2, 6 , Timothy A Chan 1, 7 , Jason T Huse 3, 6
Nature Communications ( IF 14.7 ) Pub Date : 2019-02-26 , DOI: 10.1038/s41467-019-08905-8
Yuxiang Wang 1 , Jie Yang 2 , Aaron T Wild 1 , Wei H Wu 1 , Rachna Shah 1 , Carla Danussi 3 , Gregory J Riggins 4 , Kasthuri Kannan 5 , Erik P Sulman 2, 6 , Timothy A Chan 1, 7 , Jason T Huse 3, 6
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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.
中文翻译：
G-四链体DNA驱动基因组不稳定，并代表ATRX缺乏的恶性神经胶质瘤中的可靶向分子异常。
ATRX（α-地中海贫血智力障碍X连锁）的突变失活代表了恶性神经胶质瘤的大子集中的定义性分子改变。然而，ATRX缺乏的致病性后果及其治疗靶标的易处理机制尚不清楚。在这里，我们报告在等基因神经胶质瘤模型系统中ATRX丢失通过G-四链体（G4）DNA二级结构诱导复制压力和DNA损伤。而且，这些影响与随着时间的推移获得与疾病有关的拷贝数改变有关。然后，我们在体外和体内证明ATRX缺乏选择性地增强了化学G4稳定后的DNA损伤和细胞死亡。最后，我们证明在ATRX缺乏的情况下，G4稳定与其他破坏DNA的疗法（包括电离辐射）具有协同作用。
更新日期：2019-02-26
中文翻译：
G-四链体DNA驱动基因组不稳定，并代表ATRX缺乏的恶性神经胶质瘤中的可靶向分子异常。
ATRX（α-地中海贫血智力障碍X连锁）的突变失活代表了恶性神经胶质瘤的大子集中的定义性分子改变。然而，ATRX缺乏的致病性后果及其治疗靶标的易处理机制尚不清楚。在这里，我们报告在等基因神经胶质瘤模型系统中ATRX丢失通过G-四链体（G4）DNA二级结构诱导复制压力和DNA损伤。而且，这些影响与随着时间的推移获得与疾病有关的拷贝数改变有关。然后，我们在体外和体内证明ATRX缺乏选择性地增强了化学G4稳定后的DNA损伤和细胞死亡。最后，我们证明在ATRX缺乏的情况下，G4稳定与其他破坏DNA的疗法（包括电离辐射）具有协同作用。
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