USP7 Cooperates with SCML2 To Regulate the Activity of PRC1

Abstract

USP7 is a protein deubiquitinase with an essential role in development. Here, we provide evidence that USP7 regulates the activity of Polycomb repressive complex 1 (PRC1) in coordination with SCML2. There are six versions of PRC1 defined by the association of one of the PCGF homologues (PCGF1 to PCGF6) with the common catalytic subunit RING1B. First, we show that SCML2, a Polycomb group protein that associates with PRC1.2 (containing PCGF2/MEL18) and PRC1.4 (containing PCGF4/ BMI1), modulates the localization of USP7 and bridges USP7 with PRC1.4, allowing for the stabilization of BMI1. Chromatin immunoprecipitation (ChIP) experiments demonstrate that USP7 is found at SCML2 and BMI1 target genes. Second, inhibition of USP7 leads to a reduction in the level of ubiquitinated histone H2A (H2Aub), the catalytic product of PRC1 and key for its repressive activity. USP7 regulates the posttranslational status of RING1B and BMI1, a specific component of PRC1.4. Thus, not only does USP7 stabilize PRC1 components, its catalytic activity is also necessary to maintain a functional PRC1, thereby ensuring appropriate levels of repressive H2Aub.

Stabilization of histone demethylase PHF8 by USP7 promotes breast carcinogenesis

“…To test this, qChIP experiments were performed and the recruitment of USP7 on the above-described PHF8 target genes was examined in MCF-7 cells. We did not detect the occupancy of USP7 on the promoters of CCNA2, DEP-DC1B, TGFB2, and CCNE2 genes, although we did detect the presence of USP7 on the promoters of MED23 and RPS7 genes ( Figure 4F), as reported by others (37). These results favor the argument that USP7 regulates the expression of PHF8 target genes through stabilizing PHF8.…”

The Deubiquitinating Enzyme USP7 Regulates Androgen Receptor Activity by Modulating Its Binding to Chromatin

“…Recently, USP10 was reported to deubiquitinate histone variant H2A.Z, which is required for AR transcriptional activation (43,44). Because USP7 is proposed to modulate H2A and H2B ubiquitination via direct or indirect pathways (45,46), the effect of USP7 on AR-chromatin binding and transcriptional activity could be a combinatorial consequence of both direct deubiquitination of AR and indirect deubiquitination of histones.…”

Undercover: gene control by metabolites and metabolic enzymes

“…Whereas USP7 has been implicated in Polycomb repression in human cells, the potential role of GMPS has not been examined yet. Research in mammalian cells revealed that USP7 associates with selective PcG proteins, thereby modulating their level and activity, including H2Aub (Maertens et al 2010;Frappier and Verrijzer 2011;Lecona et al 2015). Thus, USP7 can create a repressive chromatin environment by deubiquitylation of H2Bub (a mark of active chromatin) and stimulates H2Aub (a mark of repressed chromatin).…”