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Sci Transl Med. 2016 Mar 2;8(328):328ra28. doi: 10.1126/scitranslmed.aac8228.

ATRX loss promotes tumor growth and impairs nonhomologous end joining DNA repair in glioma.

Author information

1
Division of Pediatric Hematology-Oncology, Department of Pediatrics, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA. Departments of Neurosurgery and Cell and Developmental Biology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
2
Departments of Neurosurgery and Cell and Developmental Biology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
3
Divisions of Molecular Pathology and Cancer Therapeutics, Institute of Cancer Research, London SM2 5NG, UK.
4
Department of Pathology, Johns Hopkins University, Baltimore, MD 21287, USA.
5
Department of Biostatistics, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
6
Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
7
Department of Biology, University of Rochester, Rochester, NY 14627, USA.
8
Departments of Pathology and Urology, Johns Hopkins University, Baltimore, MD 21287, USA.
9
Departments of Neurosurgery and Cell and Developmental Biology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA. mariacas@med.umich.edu.

Abstract

Recent work in human glioblastoma (GBM) has documented recurrent mutations in the histone chaperone protein ATRX. We developed an animal model of ATRX-deficient GBM and showed that loss of ATRX reduces median survival and increases genetic instability. Further, analysis of genome-wide data for human gliomas showed that ATRX mutation is associated with increased mutation rate at the single-nucleotide variant (SNV) level. In mouse tumors, ATRX deficiency impairs nonhomologous end joining and increases sensitivity to DNA-damaging agents that induce double-stranded DNA breaks. We propose that ATRX loss results in a genetically unstable tumor, which is more aggressive when left untreated but is more responsive to double-stranded DNA-damaging agents, resulting in improved overall survival.

PMID:
26936505
PMCID:
PMC5381643
DOI:
10.1126/scitranslmed.aac8228
[Indexed for MEDLINE]
Free PMC Article

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