The ATM repair pathway inhibits RNA polymerase I transcription in response to chromosome breaks
The ATM repair pathway inhibits RNA polymerase I transcription in response to chromosome breaks
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DOI：
10.1038/nature05842
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发表时间：
2007-06-07
期刊：
影响因子：
64.8
通讯作者：
Casellas, Rafael
中科院分区：
文献类型：
--
作者：
Kruhlak, Michael;Crouch, Elizabeth E.;Casellas, Rafael
DNA损伤干扰DNA和RNA聚合酶活性。环丁烷嘧啶二聚体和紫外线照射产生的光产物导致RNA聚合酶II停滞，转录偶联修复酶激活和RNA合成抑制（1，2）。在细胞周期的S期，复制叉与受损DNA的碰撞阻断了正在进行的DNA复制，同时也触发了抑制远处复制起点的生物化学信号（3，4）。转录机制是否受到DNA双链断裂的影响仍然是一个长期存在的问题。在这里，我们监测RNA聚合酶I（Pol I）的活性在小鼠细胞暴露于遗传毒性的压力，并表明，诱导DNA断裂导致一个短暂的抑制Pol I转录。令人惊讶的是，我们发现Pol I抑制本身不是DNA损伤的直接结果，而是由ATM激酶活性和修复因子蛋白NBS 1（也称为NLRP 2）和MDC 1介导的。使用活细胞成像，激光微照射，和光漂白技术，我们证明，DNA损伤干扰Pol I起始复合物的组装，并导致过早的位移延长全酶从核糖体DNA。我们的数据揭示了一种新型的ATM/NBS 1/MDC 1依赖性途径，该途径可以响应染色体断裂而关闭核糖体基因转录。
DNA lesions interfere with DNA and RNA polymerase activity. Cyclobutane pyrimidine dimers and photoproducts generated by ultraviolet irradiation cause stalling of RNA polymerase II, activation of transcription-coupled repair enzymes, and inhibition of RNA synthesis(1,2). During the S phase of the cell cycle, collision of replication forks with damaged DNA blocks ongoing DNA replication while also triggering a biochemical signal that suppresses the firing of distant origins of replication(3,4). Whether the transcription machinery is affected by the presence of DNA double-strand breaks remains a long-standing question. Here we monitor RNA polymerase I ( Pol I) activity in mouse cells exposed to genotoxic stress and show that induction of DNA breaks leads to a transient repression in Pol I transcription. Surprisingly, we find Pol I inhibition is not itself the direct result of DNA damage but is mediated by ATM kinase activity and the repair factor proteins NBS1 ( also known as NLRP2) and MDC1. Using live-cell imaging, laser micro-irradiation, and photobleaching technology we demonstrate that DNA lesions interfere with Pol I initiation complex assembly and lead to a premature displacement of elongating holoenzymes from ribosomal DNA. Our data reveal a novel ATM/NBS1/MDC1-dependent pathway that shuts down ribosomal gene transcription in response to chromosome breaks.