Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Cancer Cell. 2010 Dec 14;18(6):619-29. doi: 10.1016/j.ccr.2010.10.034.
Maintenance of genomic integrity is essential for adult tissue homeostasis and defects in the DNA-damage response (DDR) machinery are linked to numerous pathologies including cancer. Here, we present evidence that the DDR exerts tumor suppressor activity in gliomas. We show that genes encoding components of the DDR pathway are frequently altered in human gliomas and that loss of elements of the ATM/Chk2/p53 cascade accelerates tumor formation in a glioma mouse model. We demonstrate that Chk2 is required for glioma response to ionizing radiation in vivo and is necessary for DNA-damage checkpoints in the neuronal stem cell compartment. Finally, we observed that the DDR is constitutively activated in a subset of human GBMs, and such activation correlates with regions of hypoxia.
维持基因组完整性对于成人组织稳态至关重要，而 DNA 损伤反应 (DDR) 机制的缺陷与包括癌症在内的许多病理学有关。在这里，我们提供了证据表明 DDR 在神经胶质瘤中发挥肿瘤抑制活性。我们表明，编码 DDR 途径组成部分的基因在人类神经胶质瘤中经常发生改变，并且 ATM/Chk2/p53 级联的元件缺失会加速神经胶质瘤小鼠模型中的肿瘤形成。我们证明 Chk2 对于体内神经胶质瘤对电离辐射的反应是必需的，并且对于神经元干细胞区室中的 DNA 损伤检查点也是必需的。最后，我们观察到 DDR 在一部分人类 GBM 中持续激活，这种激活与缺氧区域相关。
