GMP Synthetase Stimulates Histone H2B Deubiquitylation by the Epigenetic Silencer USP7

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.

Proteomics Analysis of Ring1B/Rnf2 Interactors Identifies a Novel Complex with the Fbxl10/Jhdm1B Histone Demethylase and the Bcl6 Interacting Corepressor

“…The histone H3 Lys-9 methyltransferase Setdb1, together with its activating partner, mAM (46), was also identified in the analysis, although the sequence coverage of the corresponding peptides was relatively low, possibly indicating non-stoichiometric amounts or a low abundance complex. Another interesting putative new interactor is the ubiquitin protease encoded by the Usp7 gene, which has been shown in flies to interact genetically with PcG genes (47). These and other new proteins shown in Table I and Fig.…”

Pharmacological targeting of guanosine monophosphate synthase suppresses melanoma cell invasion and tumorigenicity

“…[21][22][23][24] However, the ability of exogenous guanosine to fully revert all phenotypes caused by GMPS depletion in vitro (Figure 1) strongly suggests that guanylate biosynthetic function has the most important role in GMPS-dependent maintenance of invasive and tumorigenic phenotypes of melanoma cells.…”

“…[18][19][20] Mammalian GMPS has been the subject of several studies addressing its unconventional (GMP-unrelated) roles in the regulation of activity of ubiquitin-specific protease 7 (USP7). [21][22][23][24] However, because of the newly revealed importance of guanylate metabolism in control of melanoma cell invasion and tumorigenicity, 8 GMPS emerges as an attractive target for anti-cancer therapy.…”

Early adipogenesis is regulated through USP7-mediated deubiquitination of the histone acetyltransferase TIP60

“…Two molecular mechanisms, which are not mutually exclusive, have been described that can regulate USP7 activity: interaction with specific proteins and PTM. Studies in D. melanogaster and human cells found the metabolic enzyme GMP synthase to stimulate the ability of USP7 to deubiquitinate histone H2B [30][31][32] , whereas the TSPYL5 protein can inhibit the activity of USP7 towards p53 in mammalian cells 33 . Besides these two proteins, Sowa et al 34 identified 430 additional USP7-interacting proteins using a global proteomic analysis.…”