Impaired tRNA nuclear export links DNA damage and cell-cycle checkpoint
Impaired tRNA nuclear export links DNA damage and cell-cycle checkpoint
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DOI：
10.1016/j.cell.2007.09.042
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发表时间：
2007-11-30
期刊：
影响因子：
64.5
通讯作者：
Emili, Andrew
中科院分区：
文献类型：
--
作者：
Ghavidel, Ata;Kislinger, Thomas;Emili, Andrew
为了应对基因毒性应激，细胞会引起大量的生理反应，这些反应共同旨在增强活力并维持基因组的完整性。在这里，我们报道了 DNA 损伤后，未剪接的 tRNA 在酿酒酵母的细胞核中迅速积累。这种反应需要完整的 MEC1 和 RAD53 依赖性信号通路，该通路通过核转运蛋白 Los1 向细胞质的差异重定位来阻碍含内含子 tRNA 的核输出。未剪接的 tRNA 在细胞核中的积累会发出 Gcn4 转录因子激活的信号，而 Gcn4 转录因子反过来又通过延迟细胞周期蛋白 Cln2 的积累而导致细胞周期停滞在 G1 期。因此，受调节的核质 tRNA 运输构成了对 DNA 损伤的完整生理适应。这些数据进一步说明了不同功能模块（即 tRNA 核质运输、蛋白质合成和检查点执行）之间的信号介导串扰如何实现 tRNA 生物发生和细胞周期进程的功能耦合。
In response to genotoxic stress, cells evoke a plethora of physiological responses collectively aimed at enhancing viability and maintaining the integrity of the genome. Here, we report that unspliced tRNA rapidly accumulates in the nuclei of yeast Saccharomyces cerevisiae after DNA damage. This response requires an intact MEC1- and RAD53-dependent signaling pathway that impedes the nuclear export of intron-containing tRNA via differential relocalization of the karyopherin Los1 to the cytoplasm. The accumulation of unspliced tRNA in the nucleus signals the activation of Gcn4 transcription factor, which, in turn, contributes to cell-cycle arrest in G1 in part by delaying accumulation of the cyclin Cln2. The regulated nucleocytoplasmic tRNA trafficking thus constitutes an integral physiological adaptation to DNA damage. These data further illustrate how signal-mediated crosstalk between distinct functional modules, namely, tRNA nucleocytoplasmic trafficking, protein synthesis, and checkpoint execution, allows for functional coupling of tRNA biogenesis and cell-cycle progression.