A genetic screen identifies the Triple T complex required for DNA damage signaling and ATM and ATR stability
A genetic screen identifies the Triple T complex required for DNA damage signaling and ATM and ATR stability
复制标题
DOI：
10.1101/gad.1934210
复制
发表时间：
2010-09-10
影响因子：
10.5
通讯作者：
Elledge, Stephen J.
中科院分区：
文献类型：
--
作者：
Hurov, Kristen E.;Cotta-Ramusino, Cecilia;Elledge, Stephen J.
为了应对DNA损伤，细胞激活一个复杂的信号转导网络，称为DNA损伤反应（DDR）。为了加强我们目前对DDR网络的理解，我们进行了全基因组RNAi筛选，以确定抵抗电离辐射（IR）所需的基因。沿着一些已知的DDR基因，我们发现了大量的新基因，其耗尽导致细胞对IR的敏感性。在这里，我们描述了TTI 1（Tel两个相互作用蛋白1）和TTI 2作为哺乳动物中DDR的高度保守的调节剂。TTI 1和TTI 2保护细胞免受自发性DNA损伤，并且是建立S内和G2/M检查点所必需的。TTI 1和TTI 2存在于多个复合物中，包括与TEL 2（端粒维持2）的2-MDa复合物（称为三重T复合物），以及磷酸肌醇-3-激酶相关蛋白激酶（PIKK），例如共济失调毛细血管扩张突变型（ATM）。TTT复合物的组分相互依赖，并且充当PIKK丰度和检查点信号传导的关键调节剂。
In response to DNA damage, cells activate a complex signal transduction network called the DNA damage response (DDR). To enhance our current understanding of the DDR network, we performed a genome-wide RNAi screen to identify genes required for resistance to ionizing radiation (IR). Along with a number of known DDR genes, we discovered a large set of novel genes whose depletion leads to cellular sensitivity to IR. Here we describe TTI1 (Tel two-interacting protein 1) and TTI2 as highly conserved regulators of the DDR in mammals. TTI1 and TTI2 protect cells from spontaneous DNA damage, and are required for the establishment of the intra-S and G2/M checkpoints. TTI1 and TTI2 exist in multiple complexes, including a 2-MDa complex with TEL2 (telomere maintenance 2), called the Triple T complex, and phosphoinositide-3-kinase-related protein kinases (PIKKs) such as ataxia telangiectasia-mutated (ATM). The components of the TTT complex are mutually dependent on each other, and act as critical regulators of PIKK abundance and checkpoint signaling.