DNA damage checkpoint triggers autophagy to regulate the initiation of anaphase
DNA damage checkpoint triggers autophagy to regulate the initiation of anaphase
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DOI：
10.1073/pnas.1218065109
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发表时间：
2013-01-02
影响因子：
11.1
通讯作者：
Haber, James E.
中科院分区：
文献类型：
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作者：
Dotiwala, Farokh;Eapen, Vinay V.;Haber, James E.
遭受单个未修复的双链断裂（DSB）的芽殖酵母细胞触发Mec 1（ATR）依赖性DNA损伤反应，导致它们在分裂后期前停滞12-15小时。在这里，我们发现，超活化的细胞质到空泡（CVT）自噬途径导致永久G2/M停滞的细胞与一个单一的DSB，这是反映在核排斥的Esp 1和Pds 1。瞬时重新定位的Pds 1也被认为是在野生型细胞缺乏液泡蛋白酶活性诱导后的DSB。即使Rad 53的DNA损伤依赖性磷酸化减少，逮捕仍然存在。永久性停滞可以通过阻断自噬，通过删除空泡蛋白酶Prb 1，或通过用SV 40核定位信号驱动Esp 1进入细胞核来克服。DNA损伤引起的自噬可以通过三种不同的方式诱导：通过删除高尔基体相关逆行蛋白复合物（GARP），通过添加雷帕霉素，或通过显性ATG 13 - 8 SA突变的过表达。
Budding yeast cells suffering a single unrepaired double-strand break (DSB) trigger the Mec1 (ATR)-dependent DNA damage response that causes them to arrest before anaphase for 12-15 h. Here we find that hyperactivation of the cytoplasm-to-vacuole (CVT) autophagy pathway causes the permanent G2/M arrest of cells with a single DSB that is reflected in the nuclear exclusion of both Esp1 and Pds1. Transient relocalization of Pds1 is also seen in wild-type cells lacking vacuolar protease activity after induction of a DSB. Arrest persists even as the DNA damage-dependent phosphorylation of Rad53 diminishes. Permanent arrest can be overcome by blocking autophagy, by deleting the vacuolar protease Prb1, or by driving Esp1 into the nucleus with a SV40 nuclear localization signal. Autophagy in response to DNA damage can be induced in three different ways: by deleting the Golgi-associated retrograde protein complex (GARP), by adding rapamycin, or by overexpression of a dominant ATG13-8SA mutation.