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

2016; American Association for the Advancement of Science; Volume: 8; Issue: 328 Linguagem: Inglês

10.1126/scitranslmed.aac8228

1946-6242

Carl Koschmann, Anda‐Alexandra Calinescu, Felipe J. Núñez, Alan Mackay, Janet Fazal-Salom, Danièl 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 D. Appelman, David O. Ferguson, Vera Gorbunova, Alan K. Meeker, Chris Jones, Pedro R. Löwenstein, María G. Castro,

Mitochondrial Function and Pathology

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.