Loss of ATRX suppresses ATM dependent DNA damage repair by modulating H3K9me3 to enhance temozolomide sensitivity in glioma

Mutations in ATRX constitute the most prevalent genetic abnormalities in gliomas. The presence of ATRX mutations in glioma serves as a marker of better prognosis with longer patient survival although the underlying mechanisms are poorly understood. In the present study, we found that ATRX biological...

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Bibliographic Details
Published in:Cancer letters 2018-04, Vol.419, p.280-290
Main Authors: Han, Bo, Cai, Jinquan, Gao, Weida, Meng, Xiangqi, Gao, Fei, Wu, Pengfei, Duan, Chunbin, Wang, Ruijia, Dinislam, Magafurov, Lin, Lin, Kang, Chunsheng, Jiang, Chuanlu
Format: Article
Language:English
Subjects:
Apoptosis
ATM
ATRX
Brain cancer
Cell proliferation
Chemoresistance
CRISPR
DNA biosynthesis
DNA damage
DNA damage repair
DNA methylation
DNA repair
Genetic abnormalities
Glioblastoma
Glioma
Glioma cells
Inactivation
Kinases
Mimicry
Mutation
Phosphorylation
Proteins
Sensitivity
Temozolomide
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Summary:Mutations in ATRX constitute the most prevalent genetic abnormalities in gliomas. The presence of ATRX mutations in glioma serves as a marker of better prognosis with longer patient survival although the underlying mechanisms are poorly understood. In the present study, we found that ATRX biological function was significantly involved in DNA replication and repair. CRISPR/Cas9-mediated genetic inactivation of ATRX induced inhibition of cell proliferation, invasion and vasculogenic mimicry. In addition, temozolomide (TMZ) treatment induced greater DNA damage and apoptotic changes in ATRX knockout glioma cells. Moreover, we confirmed that ATRX knockout resulted in a failure to trigger ATM phosphorylation and finally restrained the activation of downstream proteins of the ATM pathway. The ATM-associated DNA repair pathway was extensively compromised in ATRX knockout cells owing to decreased histone H3K9me3 availability. Public databases also showed that patients with low ATRX expression exhibited preferable overall survival and profited more from TMZ treatment. These data suggest that ATRX is involved in DNA damage repair by regulating the ATM pathway and might serve as a prognostic maker in predicting TMZ chemosensitivity. •ATRX knockout downregulates glioma cell malignant behaviors.•ATRX regulates DNA damage repair through the ATM signaling pathway.•ATRX expression correlates with the chemosensitivity of patients with GBM.
ISSN:0304-3835
1872-7980
DOI:10.1016/j.canlet.2018.01.056