Schaetzlein Sonja, Kodandaramireddy N R, Ju Zhenyu, Lechel Andre, Stepczynska Anna, Lilli Dana R, Clark Alan B, Rudolph Cornelia, Kuhnel Florian, Wei Kaichun, Schlegelberger Brigitte, Schirmacher Peter, Kunkel Thomas A, Greenberg Roger A, Edelmann Winfried, Rudolph K Lenhard
Department of Gastroenterology, Hepatology and Endocrinology, Medical School Hannover, 30625 Hanover, Germany.
Cell. 2007 Sep 7;130(5):863-77. doi: 10.1016/j.cell.2007.08.029.
Exonuclease-1 (EXO1) mediates checkpoint induction in response to telomere dysfunction in yeast, but it is unknown whether EXO1 has similar functions in mammalian cells. Here we show that deletion of the nuclease domain of Exo1 reduces accumulation of DNA damage and DNA damage signal induction in telomere-dysfunctional mice. Exo1 deletion improved organ maintenance and lifespan of telomere-dysfunctional mice but did not increase chromosomal instability or cancer formation. Deletion of Exo1 also ameliorated the induction of DNA damage checkpoints in response to gamma-irradiation and conferred cellular resistance to 6-thioguanine-induced DNA damage. Exo1 deletion impaired upstream induction of DNA damage responses by reducing ssDNA formation and the recruitment of Replication Protein A (RPA) and ATR at DNA breaks. Together, these studies provide evidence that EXO1 contributes to DNA damage signal induction in mammalian cells, and deletion of Exo1 can prolong survival in the context of telomere dysfunction.
核酸外切酶1（EXO1）介导酵母中对端粒功能障碍的检查点诱导，但EXO1在哺乳动物细胞中是否具有类似功能尚不清楚。在此我们表明，Exo1核酸酶结构域的缺失减少了端粒功能障碍小鼠中DNA损伤的积累和DNA损伤信号诱导。Exo1缺失改善了端粒功能障碍小鼠的器官维持和寿命，但未增加染色体不稳定性或癌症形成。Exo1缺失还改善了对γ射线照射的DNA损伤检查点的诱导，并赋予细胞对6-硫鸟嘌呤诱导的DNA损伤的抗性。Exo1缺失通过减少单链DNA形成以及DNA断裂处复制蛋白A（RPA）和ATR的募集，损害了DNA损伤反应的上游诱导。总之，这些研究提供了证据，表明EXO1在哺乳动物细胞中有助于DNA损伤信号诱导，并且Exo1的缺失可以在端粒功能障碍的情况下延长生存期。
