Bredemeyer Andrea L, Sharma Girdhar G, Huang Ching-Yu, Helmink Beth A, Walker Laura M, Khor Katrina C, Nuskey Beth, Sullivan Kathleen E, Pandita Tej K, Bassing Craig H, Sleckman Barry P
Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
Nature. 2006 Jul 27;442(7101):466-70. doi: 10.1038/nature04866. Epub 2006 Jun 14.
The ATM (ataxia-telangiectasia mutated) protein kinase mediates early cellular responses to DNA double-strand breaks (DSBs) generated during metabolic processes or by DNA-damaging agents. ATM deficiency leads to ataxia-telangiectasia, a disease marked by lymphopenia, genomic instability and an increased predisposition to lymphoid malignancies with chromosomal translocations involving lymphocyte antigen receptor loci. ATM activates cell-cycle checkpoints and can induce apoptosis in response to DNA DSBs. However, defects in these pathways of the DNA damage response cannot fully account for the phenotypes of ATM deficiency. Here, we show that ATM also functions directly in the repair of chromosomal DNA DSBs by maintaining DNA ends in repair complexes generated during lymphocyte antigen receptor gene assembly. When coupled with the cell-cycle checkpoint and pro-apoptotic activities of ATM, these findings provide a molecular explanation for the increase in lymphoid tumours with translocations involving antigen receptor loci associated with ataxia-telangiectasia.
ATM（共济失调毛细血管扩张症突变）蛋白激酶介导细胞对代谢过程中产生的或DNA损伤剂导致的DNA双链断裂（DSB）的早期反应。ATM缺陷会导致共济失调毛细血管扩张症，这是一种以淋巴细胞减少、基因组不稳定以及易患伴有涉及淋巴细胞抗原受体基因座染色体易位的淋巴恶性肿瘤为特征的疾病。ATM激活细胞周期检查点，并能在DNA双链断裂时诱导细胞凋亡。然而，DNA损伤反应这些途径中的缺陷并不能完全解释ATM缺陷的表型。在这里，我们表明，ATM还通过维持淋巴细胞抗原受体基因组装过程中产生的修复复合物中的DNA末端，直接参与染色体DNA双链断裂的修复。当与ATM的细胞周期检查点和促凋亡活性相结合时，这些发现为共济失调毛细血管扩张症相关的、伴有涉及抗原受体基因座易位的淋巴肿瘤增加提供了分子解释。
