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Vol. 19, Issue 8, 3554-3563, August 2008

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The PHD Domain of Np95 (mUHRF1) Is Involved in Large-Scale Reorganization of Pericentromeric Heterochromatin

Roberto Papait^*,, Christian Pistore^*,, Ursula Grazini, Federica Babbio^*, Sara Cogliati^*, Daniela Pecoraro^*, Laurent Brino^,||, Anne-Laure Morand^,||, Anne-Marie Dechampesme^,||, Fabio Spada^¶, Heinrich Leonhardt^¶, Fraser McBlane, Pierre Oudet^,||, and Ian Marc Bonapace^*,

*Department of Structural and Functional Biology, University of Insubria, 21052 Busto Arsizio (VA), Italy; Department of Experimental Oncology, European Institute of Oncology, 20141 Milano, Italy; ^¶BioCenter and Center for Integrated Protein Science (CIPS), Ludwig-Maximilians-Universität München (LMU), D-82152 Planegg-Martinsried Munich, Germany; Département de Biologie du Cancer, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Institut National de la Santé et de la Recherche Médicale U596, Centre National de la Recherche Scientifique Unité Mixte de Recherche 7104, Université Louis Pasteur Strasbourg, 67400 Illkirch Cedex, Strasbourg, France; ^||Tranfected Cell Array Platform, Cancéropôle du Grand Est, 67400 Illkirch Cedex, Strasbourg, France

Submitted October 22, 2007; Revised May 12, 2008; Accepted May 16, 2008
Monitoring Editor: Yixian Zheng

Heterochromatic chromosomal regions undergo large-scale reorganization and progressively aggregate, forming chromocenters. These are dynamic structures that rapidly adapt to various stimuli that influence gene expression patterns, cell cycle progression, and differentiation. Np95-ICBP90 (m- and h-UHRF1) is a histone-binding protein expressed only in proliferating cells. During pericentromeric heterochromatin (PH) replication, Np95 specifically relocalizes to chromocenters where it highly concentrates in the replication factories that correspond to less compacted DNA. Np95 recruits HDAC and DNMT1 to PH and depletion of Np95 impairs PH replication. Here we show that Np95 causes large-scale modifications of chromocenters independently from the H3:K9 and H4:K20 trimethylation pathways, from the expression levels of HP1, from DNA methylation and from the cell cycle. The PHD domain is essential to induce this effect. The PHD domain is also required in vitro to increase access of a restriction enzyme to DNA packaged into nucleosomal arrays. We propose that the PHD domain of Np95-ICBP90 contributes to the opening and/or stabilization of dense chromocenter structures to support the recruitment of modifying enzymes, like HDAC and DNMT1, required for the replication and formation of PH.

These authors have equally contributed to the work.

Address correspondence to: Ian Marc Bonapace (ian.bonapace{at}uninsubria.it)

Abbreviations used: DAPI, 4,6-diamidino-2-phenylindole; DNMT1, DNA methyltransferase 1; H3:K9met3, tri-methylated lysine 9 of histone H3; H4:K20met3, tri-methylated lysine 20 of histone H4; pHDB, PH duplication body; RNAi, RNA interference; siRNA, small interfering RNA oligonucleotides.

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