Histone H2A deubiquitinase activity of the Polycomb repressive complex PR-DUB
Johanna C. Scheuermann,Andres Gaytan de Ayala Alonso,Katarzyna Oktaba,Nga Ly-Hartig,Robert K. McGinty,Sven Fraterman,Matthias Wilm,Tom W. Muir,Jürg Müller +8 more
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TLDR
It is shown that the uncharacterized Drosophila PcG gene calypso encodes the ubiquitin carboxy-terminal hydrolase BAP1, and Polycomb gene silencing may entail a dynamic balance between H2A ubiquitination by PRC1 and dRAF, and H 2A deubiquitinationBy PR-DUB.Abstract:
Polycomb group (PcG) proteins are transcriptional repressors that modify chromatin and regulate important developmental genes. One chromatin-modifying activity associated with Polycomb is an enzyme that ubiquitinates histone H2A. Here, Scheuermann et al. find a Drosophila PcG complex with H2A deubiquitination activity that is important for gene repression in vivo. Polycomb gene silencing may thus involve a dynamic balance between H2A ubiquitination and deubiquitination. Polycomb group (PcG) proteins are transcriptional repressors that modify chromatin and regulate important developmental genes. One PcG-associated, chromatin-modifying activity is an enzyme that ubiquitinates histone H2A of chromatin. Here, a fruitfly PcG complex that is associated with H2A deubiquitination, and thereby with gene repression, is identified. PcG-mediated gene silencing might thus involve a dynamic balance between ubiquitination and deubiquitination of H2A. Polycomb group (PcG) proteins are transcriptional repressors that control processes ranging from the maintenance of cell fate decisions and stem cell pluripotency in animals to the control of flowering time in plants1,2,3,4,5,6. In Drosophila, genetic studies identified more than 15 different PcG proteins that are required to repress homeotic (HOX) and other developmental regulator genes in cells where they must stay inactive1,7,8. Biochemical analyses established that these PcG proteins exist in distinct multiprotein complexes that bind to and modify chromatin of target genes1,2,3,4. Among those, Polycomb repressive complex 1 (PRC1) and the related dRing-associated factors (dRAF) complex contain an E3 ligase activity for monoubiquitination of histone H2A (refs 1–4). Here we show that the uncharacterized Drosophila PcG gene calypso encodes the ubiquitin carboxy-terminal hydrolase BAP1. Biochemically purified Calypso exists in a complex with the PcG protein ASX, and this complex, named Polycomb repressive deubiquitinase (PR-DUB), is bound at PcG target genes in Drosophila. Reconstituted recombinant Drosophila and human PR-DUB complexes remove monoubiquitin from H2A but not from H2B in nucleosomes. Drosophila mutants lacking PR-DUB show a strong increase in the levels of monoubiquitinated H2A. A mutation that disrupts the catalytic activity of Calypso, or absence of the ASX subunit abolishes H2A deubiquitination in vitro and HOX gene repression in vivo. Polycomb gene silencing may thus entail a dynamic balance between H2A ubiquitination by PRC1 and dRAF, and H2A deubiquitination by PR-DUB.read more
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The Polycomb complex PRC2 and its mark in life
Raphaël Margueron,Danny Reinberg +1 more
TL;DR: This work has uncovered a role for non-coding RNA in the recruitment of PRC2 to target genes, and expanded the perspectives on its function and regulation.
Journal ArticleDOI
Frequent Mutation of BAP1 in Metastasizing Uveal Melanomas
J. William Harbour,Michael D. Onken,Elisha D.O. Roberson,Shenghui Duan,Li Cao,Lori A. Worley,Katie A. Matatall,Cynthia Helms,Anne M. Bowcock +8 more
TL;DR: Exome capture coupled with massively parallel sequencing is used to search for metastasis-related mutations in highly metastatic uveal melanomas of the eye and implicate loss of BAP1 in uveAL melanoma metastasis and suggest that the BAP 1 pathway may be a valuable therapeutic target.
Journal ArticleDOI
BAP1 loss defines a new class of renal cell carcinoma
Samuel Peña-Llopis,Silvia Vega-Rubin-de-Celis,Silvia Vega-Rubin-de-Celis,Arnold Liao,Nan Leng,Andrea Pavia-Jimenez,Andrea Pavia-Jimenez,Shanshan Wang,Shanshan Wang,Toshinari Yamasaki,Toshinari Yamasaki,Leah Zhrebker,Leah Zhrebker,Sharanya Sivanand,Sharanya Sivanand,Patrick Spence,Patrick Spence,Lisa N. Kinch,Tina Hambuch,Suneer Jain,Yair Lotan,Vitaly Margulis,Arthur I. Sagalowsky,Pia Banerji Summerour,Wareef Kabbani,S. W Wendy Wong,Nick V. Grishin,Marc Laurent,Xian Jin Xie,Christian D. Haudenschild,Mark T. Ross,David R. Bentley,Payal Kapur,James Brugarolas +33 more
TL;DR: The results establish the foundation for an integrated pathological and molecular genetic classification of RCC, paving the way for subtype-specific treatments exploiting genetic vulnerabilities.
Journal ArticleDOI
Genome regulation by Polycomb and Trithorax: 70 years and counting
TL;DR: Polycomb (PcG) and Trithorax (TrxG) group proteins are evolutionarily conserved chromatin-modifying factors originally identified as part of an epigenetic cellular memory system that maintains repressed or active gene expression states.
Journal ArticleDOI
Transcriptional regulation by Polycomb group proteins.
TL;DR: The current knowledge of the PRC complexes is discussed, how they are targeted to chromatin and how the high diversity of the PcG proteins allows these complexes to influence cell identity.
References
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TL;DR: An inventory of the deubiquitinating enzymes encoded in the human genome is presented and the literature concerning these enzymes is reviewed, with particular emphasis on their function, specificity, and the regulation of their activity.
Journal ArticleDOI
Role of histone H2A ubiquitination in Polycomb silencing
Hengbin Wang,Liangjun Wang,Hediye Erdjument-Bromage,Miguel Vidal,Paul Tempst,Richard S. Jones,Yi Zhang +6 more
TL;DR: The purification and functional characterization of an E3 ubiquitin ligase complex that is specific for histone H2A is reported, and it is linked to Polycomb silencing, which is important in regulating chromatin dynamics and transcription.
Journal ArticleDOI
Histone methyltransferase activity of a Drosophila Polycomb group repressor complex
Jürg Müller,Craig M. Hart,Nicole J. Francis,Marcus L. Vargas,Aditya K. Sengupta,Aditya K. Sengupta,Brigitte Wild,Ellen L. Miller,Michael B. O'Connor,Michael B. O'Connor,Robert E. Kingston,Jeffrey A. Simon +11 more
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Journal ArticleDOI
Genome Regulation by Polycomb and Trithorax Proteins
Bernd Schuettengruber,Daniel Chourrout,Michel Vervoort,Michel Vervoort,Benjamin Leblanc,Giacomo Cavalli +5 more
TL;DR: Polycomb group (PcG) and trithorax group (trxG) proteins are critical regulators of numerous developmental genes and recent work suggests that PcG-mediated gene silencing involves noncoding RNAs and the RNAi machinery.
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