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Ref Type | Journal Article | ||||||||||||
PMID | (26936505) | ||||||||||||
Authors | Koschmann C, Calinescu AA, Nunez FJ, Mackay A, Fazal-Salom J, Thomas D, Mendez F, Kamran N, Dzaman M, Mulpuri L, Krasinkiewicz J, Doherty R, Lemons R, Brosnan-Cashman JA, Li Y, Roh S, Zhao L, Appelman H, Ferguson D, Gorbunova V, Meeker A, Jones C, Lowenstein PR, Castro MG | ||||||||||||
Title | ATRX loss promotes tumor growth and impairs nonhomologous end joining DNA repair in glioma. | ||||||||||||
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Abstract Text | 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. |