Restoration of ATM Expression in DNA-PKcs-Deficient Cells Inhibits Signal End Joining.
Restoration of ATM Expression in DNA-PKcs-Deficient Cells Inhibits Signal End Joining.
复制标题
DOI：
10.4049/jimmunol.1501654
复制
发表时间：
2016-04-01
期刊：
影响因子：
--
通讯作者：
Meek K
中科院分区：
文献类型：
--
作者：
Neal JA;Xu Y;Abe M;Hendrickson E;Meek K
与大多数DNA-PKcs缺陷的小鼠细胞株不同，我们在这里发现，在两种不同的人类细胞系中，DNA-PKcs的靶向删除可以消除VDJ信号端连接。虽然机制尚不明确，但在许多培养细胞系（包括本文研究的细胞系）和DNA-PKcs缺陷小鼠中，DNA-PKcs缺陷导致ATM表达自发减少。我们认为不同的ATM表达缺失可能解释了不同细胞株和动物模型中信号末端连接的差异，我们研究了ATM和/或DNA-PKcs缺失对培养的人和啮齿动物细胞株中VDJ重组的影响。令我们惊讶的是，在精通信号端连接的DNA-PKcs缺陷小鼠细胞株中，恢复ATM表达明显抑制信号端连接。相反，在缺乏信号端连接的DNA-PKcs缺陷细胞中，ATM的完全缺失增强了信号（但不编码）关节的形成。我们提出ATM有助于将信号末端限制为“经典”非同源末端连接途径。
Unlike most DNA-PKcs deficient mouse cell strains, we show here that targeted deletion of DNA-PKcs in two different human cell lines abrogates VDJ signal end joining in episomal assays. Although the mechanism is not well defined, DNA-PKcs deficiency results in spontaneous reduction of ATM expression in many cultured cell lines (including those studied here) and in DNA-PKcs deficient mice. We considered that varying loss of ATM expression might explain differences in signal end joining in different cell strains and animal models, and we investigated the impact of ATM and/or DNA-PKcs loss on VDJ recombination in cultured human and rodent cell strains. To our surprise, in DNA-PKcs deficient mouse cell strains that are proficient in signal end joining, restoration of ATM expression markedly inhibits signal end joining. In contrast, in DNA-PKcs deficient cells that are deficient in signal end joining, complete loss of ATM enhances signal (but not coding) joint formation. We propose that ATM facilitates restriction of signal ends to the “classical” non-homologous end-joining pathway.