Posttranslational arginylation enzyme Ate1 affects DNA mutagenesis by regulating stress response.
Posttranslational arginylation enzyme Ate1 affects DNA mutagenesis by regulating stress response.
复制标题
DOI：
10.1038/cddis.2016.284
复制
发表时间：
2016-09-29
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
作者：
精氨酸基转移酶1 （Ate1）介导蛋白质精氨酸化，这是一种在真核细胞中鲜为人知的蛋白质翻译后修饰（PTM）。先前的证据表明，精氨酸化可能参与应激反应，基于对单个底物的研究，传统上认为这种PTM具有抗凋亡作用。然而，我们发现精氨酸化促进细胞死亡和/或生长停滞，这取决于应激因子的性质和强度。具体来说，在酵母、小鼠和人类细胞中，ATE1基因的缺失或下调通过绕过生长停滞和抑制疾病相关应激因素（包括氧化、热、渗透应激以及暴露于重金属或辐射）下的细胞死亡事件，破坏了典型的应激反应。相反，在野生型细胞对应激反应中，细胞Ate1蛋白水平和精氨酸化活性增加。此外，Ate1蛋白的增加以依赖于其精氨酸化活性的方式直接促进细胞死亡。最后，我们发现Ate1需要在dna损伤条件下抑制酵母和哺乳动物细胞的突变频率，如紫外线照射。我们的研究阐明了Ate1/精氨酸化在应激反应中的作用，并为解释Ate1与包括癌症在内的多种疾病之间的联系提供了一种新的机制。这也是PTM的全局水平的调节能够影响DNA突变的第一个例子。
Arginyltransferase 1 (Ate1) mediates protein arginylation, a poorly understood protein posttranslational modification (PTM) in eukaryotic cells. Previous evidence suggest a potential involvement of arginylation in stress response and this PTM was traditionally considered anti-apoptotic based on the studies of individual substrates. However, here we found that arginylation promotes cell death and/or growth arrest, depending on the nature and intensity of the stressing factor. Specifically, in yeast, mouse and human cells, deletion or downregulation of the ATE1 gene disrupts typical stress responses by bypassing growth arrest and suppressing cell death events in the presence of disease-related stressing factors, including oxidative, heat, and osmotic stresses, as well as the exposure to heavy metals or radiation. Conversely, in wild-type cells responding to stress, there is an increase of cellular Ate1 protein level and arginylation activity. Furthermore, the increase of Ate1 protein directly promotes cell death in a manner dependent on its arginylation activity. Finally, we found Ate1 to be required to suppress mutation frequency in yeast and mammalian cells during DNA-damaging conditions such as ultraviolet irradiation. Our study clarifies the role of Ate1/arginylation in stress response and provides a new mechanism to explain the link between Ate1 and a variety of diseases including cancer. This is also the first example that the modulation of the global level of a PTM is capable of affecting DNA mutagenesis.
登录
查看更多内容
影响因子：
--
作者：
Eldeeb MA;Fahlman RP
通讯作者：
Fahlman RP
前列腺癌的基因表达谱揭示了多个分子途径在转移过程中的参与。
影响因子：
3.8
作者：
Chandran, Uma R.;Ma, Changqing;Dhir, Rajiv;Bisceglia, Michelle;Lyons-Weiler, Maureen;Liang, Wenjing;Michalopoulos, George;Becich, Michael;Monzon, Federico A.
通讯作者：
Monzon, Federico A.
影响因子：
1.7
作者：
JACK, DL;CHAKRABORTY, G;INGOGLIA, NA
通讯作者：
INGOGLIA, NA
影响因子：
64.8
作者：
Deardorff, Matthew A.;Bando, Masashige;Nakato, Ryuichiro;Watrin, Erwan;Itoh, Takehiko;Minamino, Masashi;Saitoh, Katsuya;Komata, Makiko;Katou, Yuki;Clark, Dinah;Cole, Kathryn E.;De Baere, Elfride;Decroos, Christophe;Di Donato, Nataliya;Ernst, Sarah;Francey, Lauren J.;Gyftodimou, Yolanda;Hirashima, Kyotaro;Hullings, Melanie;Ishikawa, Yuuichi;Jaulin, Christian;Kaur, Maninder;Kiyono, Tohru;Lombardi, Patrick M.;Magnaghi-Jaulin, Laura;Mortier, Geert R.;Nozaki, Naohito;Petersen, Michael B.;Seimiya, Hiroyuki;Siu, Victoria M.;Suzuki, Yutaka;Takagaki, Kentaro;Wilde, Jonathan J.;Willems, Patrick J.;Prigent, Claude;Gillessen-Kaesbach, Gabriele;Christianson, David W.;Kaiser, Frank J.;Jackson, Laird G.;Hirota, Toru;Krantz, Ian D.;Shirahige, Katsuhiko
通讯作者：
Shirahige, Katsuhiko
影响因子：
3.7
作者：
Leu NA;Kurosaka S;Kashina A
通讯作者：
Kashina A