Atanassov Boyko S, Evrard Yvonne A, Multani Asha S, Zhang Zhijing, Tora László, Devys Didier, Chang Sandy, Dent Sharon Y R
Department of Biochemistry and Molecular Biology, University of Texas M.D. Anderson Cancer Center, Houston, 77030, USA.
Mol Cell. 2009 Aug 14;35(3):352-64. doi: 10.1016/j.molcel.2009.06.015.
Histone acetyltransferases (HATs) play important roles in gene regulation and DNA repair by influencing the accessibility of chromatin to transcription factors and repair proteins. Here, we show that deletion of Gcn5 leads to telomere dysfunction in mouse and human cells. Biochemical studies reveal that depletion of Gcn5 or ubiquitin-specific protease 22 (Usp22), which is another bona fide component of the Gcn5-containing SAGA complex, increases ubiquitination and turnover of TRF1, a primary component of the telomeric shelterin complex. Inhibition of the proteasome or overexpression of USP22 opposes this effect. The USP22 deubiquitinating module requires association with SAGA complexes for activity, and we find that depletion of Gcn5 compromises this association in mammalian cells. Thus, our results indicate that Gcn5 regulates TRF1 levels through effects on Usp22 activity and SAGA integrity.
组蛋白乙酰转移酶（HATs）通过影响染色质对转录因子和修复蛋白的可及性，在基因调控和DNA修复中发挥重要作用。在此，我们表明Gcn5的缺失会导致小鼠和人类细胞中的端粒功能障碍。生化研究表明，Gcn5或泛素特异性蛋白酶22（Usp22）的缺失会增加端粒保护蛋白复合体的主要成分TRF1的泛素化和周转，Usp22是含Gcn5的SAGA复合体的另一个真正组成部分。蛋白酶体抑制或USP22的过表达可对抗这种效应。USP22去泛素化模块需要与SAGA复合体结合才能发挥活性，并且我们发现Gcn5的缺失会损害其在哺乳动物细胞中的这种结合。因此，我们的结果表明，Gcn5通过影响Usp22活性和SAGA完整性来调节TRF1水平。
