GMP synthetase stimulates histone H2B deubiquitylation by the epigenetic silencer USP7.
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.
van der Knaap
Jan A
JA
Department of Biochemistry, Center for Biomedical Genetics, Erasmus University Medical Center, PO Box 1738, 3000 DR Rotterdam, The Netherlands.
Kumar
B R Prashanth
BR
Moshkin
Yuri M
YM
Langenberg
Karin
K
Krijgsveld
Jeroen
J
Heck
Albert J R
AJ
Karch
François
F
Verrijzer
C Peter
CP
D000818:Animals; D019731:Carbon-Nitrogen Ligases / Q000378:metabolism / Q000502:physiology*; D002467:Cell Nucleus / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D004330:Drosophila; D029721:Drosophila Proteins / Q000378:metabolism; D010450:Endopeptidases / Q000737:chemistry* / Q000502:physiology; D005260:Female; D020868:Gene Silencing; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D047468:Immunoprecipitation; D008025:Ligases / Q000378:metabolism; D008297:Male; D009154:Mutation; D063150:Polycomb Repressive Complex 1; D011485:Protein Binding; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025801:Ubiquitin / Q000737:chemistry* / Q000378:metabolism; D064570:Ubiquitin-Specific Proteases
D002843:Chromatin; D029721:Drosophila Proteins; D006657:Histones; C066770:Pc protein, Drosophila; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; D004247:DNA; D063150:Polycomb Repressive Complex 1; D010450:Endopeptidases; D064570:Ubiquitin-Specific Proteases; D008025:Ligases; C028812:guanosine 3',5'-polyphosphate synthetases; D019731:Carbon-Nitrogen Ligases; C020828:GMP synthase (glutamine-hydrolyzing)