title: ATRX loss promotes tumor growth and impairs nonhomologous end joining DNA repair in glioma.
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.
authors.affiliation: 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.
authors.forename: Carl
authors.initials: C
authors.lastname: Koschmann
authors.affiliation: Departments of Neurosurgery and Cell and Developmental Biology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
authors.forename: Anda-Alexandra
authors.initials: AA
authors.lastname: Calinescu
authors.affiliation: Departments of Neurosurgery and Cell and Developmental Biology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
authors.forename: Felipe J
authors.initials: FJ
authors.lastname: Nunez
authors.affiliation: Divisions of Molecular Pathology and Cancer Therapeutics, Institute of Cancer Research, London SM2 5NG, UK.
authors.forename: Alan
authors.initials: A
authors.lastname: Mackay
authors.affiliation: Divisions of Molecular Pathology and Cancer Therapeutics, Institute of Cancer Research, London SM2 5NG, UK.
authors.forename: Janet
authors.initials: J
authors.lastname: Fazal-Salom
authors.affiliation: Departments of Neurosurgery and Cell and Developmental Biology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Thomas
authors.affiliation: Departments of Neurosurgery and Cell and Developmental Biology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
authors.forename: Flor
authors.initials: F
authors.lastname: Mendez
authors.affiliation: Departments of Neurosurgery and Cell and Developmental Biology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
authors.forename: Neha
authors.initials: N
authors.lastname: Kamran
authors.affiliation: Departments of Neurosurgery and Cell and Developmental Biology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
authors.forename: Marta
authors.initials: M
authors.lastname: Dzaman
authors.affiliation: Departments of Neurosurgery and Cell and Developmental Biology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
authors.forename: Lakshman
authors.initials: L
authors.lastname: Mulpuri
authors.affiliation: Departments of Neurosurgery and Cell and Developmental Biology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
authors.forename: Johnathon
authors.initials: J
authors.lastname: Krasinkiewicz
authors.affiliation: Departments of Neurosurgery and Cell and Developmental Biology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Doherty
authors.affiliation: Departments of Neurosurgery and Cell and Developmental Biology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
authors.forename: Rosemary
authors.initials: R
authors.lastname: Lemons
authors.affiliation: Department of Pathology, Johns Hopkins University, Baltimore, MD 21287, USA.
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: Brosnan-Cashman
authors.affiliation: Departments of Neurosurgery and Cell and Developmental Biology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
authors.forename: Youping
authors.initials: Y
authors.lastname: Li
authors.affiliation: Departments of Neurosurgery and Cell and Developmental Biology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
authors.forename: Soyeon
authors.initials: S
authors.lastname: Roh
authors.affiliation: Department of Biostatistics, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
authors.forename: Lili
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
authors.forename: Henry
authors.initials: H
authors.lastname: Appelman
authors.affiliation: Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
authors.forename: David
authors.initials: D
authors.lastname: Ferguson
authors.affiliation: Department of Biology, University of Rochester, Rochester, NY 14627, USA.
authors.forename: Vera
authors.initials: V
authors.lastname: Gorbunova
authors.affiliation: Departments of Pathology and Urology, Johns Hopkins University, Baltimore, MD 21287, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Meeker
authors.affiliation: Divisions of Molecular Pathology and Cancer Therapeutics, Institute of Cancer Research, London SM2 5NG, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Jones
authors.affiliation: Departments of Neurosurgery and Cell and Developmental Biology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
authors.forename: Pedro R
authors.initials: PR
authors.lastname: Lowenstein
authors.affiliation: Departments of Neurosurgery and Cell and Developmental Biology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA. mariacas@med.umich.edu.
authors.forename: Maria G
authors.initials: MG
authors.lastname: Castro
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics / Q000473:pathology*; D049109:Cell Proliferation; D033481:Chromosomes, Mammalian / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics; D004249:DNA Damage; D059766:DNA End-Joining Repair; D004265:DNA Helicases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005910:Glioma / Q000235:genetics / Q000473:pathology*; D006801:Humans; D051379:Mice; D053842:Microsatellite Instability; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D016019:Survival Analysis; D059505:Telomere Homeostasis; D019895:Transposases / Q000378:metabolism; D000075924:X-linked Nuclear Protein
chemical_list: D009687:Nuclear Proteins; D019895:Transposases; D004265:DNA Helicases; C092332:ATRX protein, human; C490462:Atrx protein, mouse; D000075924:X-linked Nuclear Protein