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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Neoplasms / genetics
  • Brain Neoplasms / pathology*
  • Cell Proliferation
  • Chromosomes, Mammalian / genetics
  • DNA Copy Number Variations / genetics
  • DNA Damage
  • DNA End-Joining Repair*
  • DNA Helicases / deficiency*
  • DNA Helicases / genetics
  • DNA Helicases / metabolism
  • Disease Models, Animal
  • Glioma / genetics
  • Glioma / pathology*
  • Humans
  • Mice
  • Microsatellite Instability
  • Mutation / genetics
  • Nuclear Proteins / deficiency*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Polymorphism, Single Nucleotide / genetics
  • Survival Analysis
  • Telomere Homeostasis
  • Transposases / metabolism
  • X-linked Nuclear Protein


  • Nuclear Proteins
  • Transposases
  • DNA Helicases
  • ATRX protein, human
  • Atrx protein, mouse
  • X-linked Nuclear Protein