ATM prevents the persistence and propagation of chromosome breaks in lymphocytes
ATM prevents the persistence and propagation of chromosome breaks in lymphocytes
复制标题
DOI：
10.1016/j.cell.2007.06.016
复制
发表时间：
2007-07-13
期刊：
影响因子：
64.5
通讯作者：
Nussenzweig, Andre
中科院分区：
文献类型：
--
作者：
Callen, Elsa;Jankovic, Mila;Nussenzweig, Andre
DNA双链断裂(DSB)诱导由共济失调-毛细血管扩张突变(ATM)激酶传递的信号，从而抑制DSB的非法连接并激活细胞周期检查点。在这里，我们表明，相当一部分成熟的ATM缺陷淋巴细胞含有端粒缺失的末端，这是由于V(D)J重组过程中末端连接失败而产生的。这些依赖RAG-1/2内切酶、末端缺失的染色体在体内外周淋巴细胞中持续至少2周，并在体外几代人中保持稳定。在具有短暂失去ATM功能的成熟淋巴细胞中，ATM激酶活性的恢复会导致染色体末端缺失的细胞的丧失。因此，维持淋巴细胞的基因组稳定性需要忠实的末端连接以及防止DSB长期持续和传播的检查点。沉默这一检查点允许淋巴样前体中V(D)J重组产生的DNA末端作为易位的底物，随后在成熟细胞中被其他方式破坏。
DNA double- strand breaks ( DSBs) induce a signal transmitted by the ataxia- telangiectasia mutated ( ATM) kinase, which suppresses illegitimate joining of DSBs and activates cell- cycle checkpoints. Here we show that a significant fraction of mature ATM- deficient lymphocytes contain telomere- deleted ends produced by failed end joining during V( D) J recombination. These RAG- 1/ 2 endonuclease- dependent, terminally deleted chromosomes persist in peripheral lymphocytes for at least 2 weeks in vivo and are stable over several generations in vitro. Restoration of ATM kinase activity in mature lymphocytes that have transiently lostATM function leads to loss of cells with terminally deleted chromosomes. Thus, maintenance of genomic stability in lymphocytes requires faithful end joining as well a checkpoint that prevents the long- term persistence and transmission of DSBs. Silencing this checkpoint permits DNA ends produced by V( D) J recombination in a lymphoid precursor to serve as substrates for translocations with chromosomes subsequently damaged by other means in mature cells.