2017年2月21日，国际核酸类重要学术期刊《Nucleic Acids Research》杂志在线发表了武汉大学生命科学学院杜海宁课题组的最新研究成果。论文题目为“Gcn5-mediated Rph1 acetylation regulates its autophagic degradation under DNA Damage Stress”(乙酰转移酶Gcn5介导的乙酰化修饰调控组蛋白去甲基化酶Rph1在DNA损伤应急下的自噬降解)。博士生李锋为论文的第一作者，杜海宁教授为论文的通讯作者。

许多与损伤修复相关基因的表达在细胞生命过程中被严格调控：在正常条件下表达被抑制，而在DNA损伤刺激下表达被激活。组蛋白去甲基化酶Rph1可以抑制很多环境应急及自噬相关基因的表达，但是Rph1在应急条件下是如何被调控的尚不清楚。课题组的研究人员发现，在DNA损伤刺激下，酿酒酵母中的组蛋白修饰酶Rph1会通过自噬途径降解，以解除对DNA损伤基因的抑制。乙酰转移酶Gcn5介导的乙酰化修饰能够有效调控Rph1的出核过程并进入胞质中的自噬体进行蛋白质降解。这种调控机制对于DNA损伤信号通路的激活和细胞内稳态环境的维持都是必需的。我们的研究提示，乙酰化介导的自噬降解途径很可能代表着一种清除受损细胞器和DNA损伤修复相关抑制因子的广泛机制。

Nucleic Acids Res:武汉大学杜海宁课题组揭示核蛋白应急条件下自噬降解新途径
Gcn5介导的乙酰化修饰调控Rph1的出核和自噬降解

原文链接：

Gcn5-mediated Rph1 acetylation regulates its autophagic degradation under DNA damage stress

原文摘要：

Histone modifiers regulate proper cellular activities in response to various environmental stress by modulating gene expression. In budding yeast, Rph1 transcriptionally represses many DNA damage or autophagy-related gene expression. However, little is known how Rph1 is regulated during these stress conditions. Here, we report that Rph1 is degraded upon DNA damage stress conditions. Notably, this degradation occurs via the autophagy pathway rather than through 26S proteasome proteolysis. Deletion of ATG genes or inhibition of vacuole protease activity compromises Rph1 turnover. We also determine that Rph1 and nuclear export protein Crm1 interact, which is required for Rph1 translocation from the nucleus to the cytoplasm. More importantly, Gcn5 directly acetylates Rph1 in vitro and in vivo, and Gcn5-containing complex, SAGA, is required for autophagic degradation of Rph1. Gcn5-mediated Rph1 acetylation is essential for the association of Rph1 with the nuclear pore protein Nup1. Finally, we show that sustaining high levels of Rph1 during DNA damage stress results in cell growth defects. Thus, we propose that Gcn5-mediated acetylation finely regulates Rph1 protein level and that autophagic degradation of Rph1 is important for cell homeostasis. Our findings may provide a general connection between DNA damage, protein acetylation and autophagy.