GMP合成酶通过表观遗传沉默因子USP7刺激组蛋白H2B去泛素化。

GMP synthetase stimulates histone H2B deubiquitylation by the epigenetic silencer USP7.

作者信息

van der Knaap Jan A, Kumar B R Prashanth, Moshkin Yuri M, Langenberg Karin, Krijgsveld Jeroen, Heck Albert J R, Karch François, Verrijzer C Peter

机构信息

Department of Biochemistry, Center for Biomedical Genetics, Erasmus University Medical Center, PO Box 1738, 3000 DR Rotterdam, The Netherlands.

出版信息

Mol Cell. 2005 Mar 4;17(5):695-707. doi: 10.1016/j.molcel.2005.02.013.

DOI:10.1016/j.molcel.2005.02.013

PMID:15749019

Abstract

The packaging of eukaryotic genomic DNA into chromatin is modulated through a range of posttranslational histone modifications. Among these, the role of histone ubiquitylation remains poorly understood. Here, we show that the essential Drosophila ubiquitin-specific protease 7 (USP7) contributes to epigenetic silencing of homeotic genes by Polycomb (Pc). We purified USP7 from embryo nuclear extracts as a stable heteromeric complex with guanosine 5'-monophosphate synthetase (GMPS). The USP7-GMPS complex catalyzed the selective deubiquitylation of histone H2B, but not H2A. Biochemical assays confirmed the tight association between USP7 and GMPS in Drosophila embryo extracts. Similar to USP7, mutations in GMPS acted as enhancers of Pc in vivo. USP7 binding to GMPS was required for histone H2B deubiquitylation and strongly augmented deubiquitylation of the human tumor suppressor p53. Thus, GMPS can regulate the activity of a ubiquitin protease. Collectively, these results implicate a biosynthetic enzyme in chromatin control via ubiquitin regulation.

摘要

真核生物基因组DNA包装成染色质的过程通过一系列翻译后组蛋白修饰来调节。其中，组蛋白泛素化的作用仍知之甚少。在此，我们表明，必不可少的果蝇泛素特异性蛋白酶7（USP7）通过多梳蛋白（Pc）促进同源异型基因的表观遗传沉默。我们从胚胎核提取物中纯化出USP7，它是与鸟苷5'-单磷酸合成酶（GMPS）形成的稳定异源复合物。USP7-GMPS复合物催化组蛋白H2B的选择性去泛素化，但不催化H2A的去泛素化。生化分析证实了果蝇胚胎提取物中USP7与GMPS之间的紧密结合。与USP7类似，GMPS中的突变在体内作为Pc的增强子起作用。USP7与GMPS的结合是组蛋白H2B去泛素化所必需的，并且强烈增强了人类肿瘤抑制因子p53的去泛素化。因此，GMPS可以调节泛素蛋白酶的活性。总体而言，这些结果表明一种生物合成酶通过泛素调节参与染色质控制。