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

Carl Koschmann, Anda Alexandra Calinescu, Felipe J. Nunez, Alan Mackay, Janet Fazal-Salom, Daniel Thomas, Flor Mendez, Neha Kamran, Marta Dzaman, Lakshman Mulpuri, Johnathon Krasinkiewicz, Robert Doherty, Rosemary Lemons, Jaqueline A. Brosnan-Cashman, Youping Li, Soyeon Roh, Lili Zhao, Henry Appelman, David Ferguson, Vera GorbunovaAlan Meeker, Chris Jones, Pedro R. Lowenstein, Maria G. Castro

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number328ra28
JournalScience translational medicine
Volume8
Issue number328
DOIs
StatePublished - Mar 2 2016

ASJC Scopus subject areas

  • Medicine(all)

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