Department of Pediatrics and Developmental Biology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
Cancer Sci. 2013 Jun;104(6):703-10. doi: 10.1111/cas.12144. Epub 2013 Apr 15.
Stalled replication forks undergo DNA double-strand breaks (DSBs) under certain conditions. However, the precise mechanism underlying DSB induction and the cellular response to persistent replication fork stalling are not fully understood. Here we show that, in response to hydroxyurea exposure, DSBs are generated in an Artemis nuclease-dependent manner following prolonged stalling with subsequent activation of the ataxia-telangiectasia mutated (ATM) signaling pathway. The kinase activity of the catalytic subunit of the DNA-dependent protein kinase, a prerequisite for stimulation of the endonuclease activity of Artemis, is also required for DSB generation and subsequent ATM activation. Our findings indicate a novel function of Artemis as a molecular switch that converts stalled replication forks harboring single-stranded gap DNA lesions into DSBs, thereby activating the ATM signaling pathway following prolonged replication fork stalling.
在某些条件下，停滞的复制叉会发生 DNA 双链断裂（DSB）。然而，DSB 诱导的确切机制以及细胞对持续复制叉停滞的反应尚不完全清楚。在这里，我们表明，在羟基脲暴露的情况下，经过长时间的停滞，随后激活共济失调毛细血管扩张突变（ATM）信号通路，以 Artemis 核酸酶依赖性的方式产生 DSB。DNA 依赖性蛋白激酶的催化亚基的激酶活性对于刺激 Artemis 的内切酶活性也是必需的，这对于 DSB 的产生和随后的 ATM 激活也是必需的。我们的发现表明 Artemis 具有作为分子开关的新功能，它将带有单链缺口 DNA 损伤的停滞复制叉转化为 DSB，从而在长时间的复制叉停滞之后激活 ATM 信号通路。
