TY - JOUR
T1 - Histone H2A deubiquitinase activity of the Polycomb repressive complex PR-DUB
AU - Scheuermann, Johanna C.
AU - De Ayala Alonso, Andrés Gaytán
AU - Oktaba, Katarzyna
AU - Ly-Hartig, Nga
AU - McGinty, Robert K.
AU - Fraterman, Sven
AU - Wilm, Matthias
AU - Muir, Tom W.
AU - Müller, Jürg
N1 - Funding Information:
Acknowledgements We thank T. Sixma and G. Buchwald for the gift of proteins, H. W. Brock, R. E. Kingston, B. Korn and B. Turner for plasmids, baculoviruses and antibodies, V. Benes, J. de Graaf, S. Müller and A. Riddell for technical support, and W. Huber and J. Gagneur for discussions. T.W.M. is supported by NIH grant RC2CA148354. J.C.S., A.G.A.A., K.O., N.L.-H. and J.M. are supported by EMBL and by grants from the DFG.
PY - 2010/5/13
Y1 - 2010/5/13
N2 - 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 1-6. 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 inactive 1,7,8. 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.
AB - 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 1-6. 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 inactive 1,7,8. 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.
UR - http://www.scopus.com/inward/record.url?scp=77952429798&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77952429798&partnerID=8YFLogxK
U2 - 10.1038/nature08966
DO - 10.1038/nature08966
M3 - Article
C2 - 20436459
AN - SCOPUS:77952429798
SN - 0028-0836
VL - 465
SP - 243
EP - 247
JO - Nature
JF - Nature
IS - 7295
ER -