ATRX loss promotes tumor growth and impairs nonhomologous end joining DNA repair in glioma
Year: 2016
Type: article
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.
Source: Science Translational Medicine
Authors: 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, Jacqueline A. Brosnan-Cashman, Youping Li, Soyeon Roh, Lili Zhao, Henry Appelman, David Ferguson, Vera Gorbunova, Alan Meeker, Chris Jones, Pedro R. Lowenstein, Maria G. Castro
Language: English
Topic: DNA Repair Mechanisms
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funders: Alex's Lemonade Stand Foundation for Childhood Cancer, St. Baldrick's Foundation, NIHR Biomedical Research Centre, Royal Marsden NHS Foundation Trust/Institute of Cancer Research, Rosetrees Trust, Brain Tumour Charity, National Institutes of Health, National Institute on Aging, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke, National Center for Advancing Translational Sciences
Awards: G1114190515, Crosstalk between glioma cells & immune cells in the tumor microenvironment: Ther, HDL-Loaded Nanoparticles for Glioma Therapeutics, Gene Therapy and the Brain: Neuroimmune Interactions, G1736410989, G1815451664, G2205775429, G2509259155, G2581612258, G279471603, Cytometry by Time of Fight (CyTOF) for High-speed Single-cell Analysis, G3236723741, G3680791898, Brain immune responses:Cellular & Molecular Mechanisms, G4433648489, Engineering the Brain Immune System for Tumor Therapy, G467313275, University of Michigan Postbaccalaureate Research Education Program (UM PREP), G524500829, G5404365437, Mechanisms of glioma growth and invasion novel therapeutic strategies, G5561615526, G5932715242, G6203608197, G645032831, Gutless Adenovirus Mediated Gene Therapy for Glioma, G8849916263, G890624478, G9000288332, University of Michigan Rogel Cancer Center Support Grant 2023-2028, Comparative genomics of longevity and Alzheimer's disease, Training in Clinical and Basic Neuroscience, Oligodendrocyte-focused rAAV gene therapy strategies for Canavan disease and Leukodystrophies
OpenAlex ID: W2292914130