Histone H2A deubiquitinase activity of the Polycomb repressive complex PR-DUB

By Johanna C. Scheuermann, Andres Gaytan de Ayala Alonso, Katarzyna Oktaba, N. Ly-Hartig, R. McGinty, Sven Fraterman, M. Wilm, T. Muir, Jürg Müller. Nature, 2010

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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 plants. 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 inactive. Biochemical analyses established that these PcG proteins exist in distinct multiprotein complexes that bind to and modify chromatin of target genes. 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.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/109e0fb82e805014efaffedf2029033b67137b4d

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Citations in the corpus

Genome Regulation by Polycomb and Trithorax: 70 Years and Counting. (2017, positive): “The Polycomb repressive deubiquitinase complex (PR-DUB) was initially identified inDrosophila and contains the ubiquitin C-terminal hydrolase Calypso (Bap1) and additional sex combs (Asx) (Scheuermann et al., 2010).”
The role of mutations in epigenetic regulators in myeloid malignancies (2012, background): “ASXL1, along with BRCA1-associated protein 1 (BAP1), is part of the Polycomb repressive deubiquitylase complex (PR-DUB), which deubiquitylates H2AK119 marks (83) leading to gene repression.”
Polycomb group proteins: multi-faceted regulators of somatic stem cells and cancer. (2010, positive): “Although less well characterized, L3MBTL and SFMBT proteins are also found in PRC1 complexes, whereas ASXL1 was recently identified in the new Polycomb Repressive H2A Deubiquitinase complex (Grimm et al., 2009; Ohtsubo et al., 2008; Peterson et al., 2004; Peterson et al., 1997; Sánchez et al., 2007;”
Occupying chromatin: Polycomb mechanisms for getting to genomic targets, stopping transcriptional traffic, and staying put (2013, background): “Further insight may derive from the dynamic role of a recently identified H2A-deubiquitylating complex, PRDUB (Figure 1F), in PcG silencing (Scheuermann et al., 2010).”
Transcriptional regulation by Polycomb group proteins (2013, background): “; and from the Novo Nordisk Foundation, the Danish Cancer Society and the Danish Council for Strategic Research (12-110503) to K.”