ATRX loss promotes tumor growth and impairs nonhomologous end joining DNA repair in glioma.
ATRX loss promotes tumor growth and impairs nonhomologous end joining DNA repair in glioma.
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ATRX 缺失会促进肿瘤生长并损害神经胶质瘤中的非同源末端连接 DNA 修复。
DOI：
10.1126/scitranslmed.aac8228
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发表时间：
2016-03-02
影响因子：
17.1
通讯作者：
Castro MG
中科院分区：
文献类型：
--
作者：
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
最近在人类胶质母细胞瘤(GBM)中的研究记录了组蛋白伴侣蛋白ATRX的反复突变。我们建立了一种ATRX缺乏的GBM的动物模型，并表明ATRX的缺失降低了中位存活率并增加了遗传不稳定性。此外，对人类胶质瘤全基因组数据的分析表明，ATRX突变与单核苷酸变异(SNV)水平上的突变率增加有关。在小鼠肿瘤中，ATRX缺乏会损害非同源末端连接(NHEJ)，并增加对诱导双链DNA断裂的DNA损伤剂的敏感性。我们认为，ATRX缺失会导致遗传不稳定的肿瘤，如果不进行治疗，肿瘤会更具侵袭性，但对双链DNA损伤剂更敏感，从而提高总体存活率。
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 show 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 non-homologous end joining (NHEJ) 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.