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J. Biol. Chem., Vol. 281, Issue 46, 35404-35412, November 17, 2006

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Protein Interactions within the Set1 Complex and Their Roles in the Regulation of Histone 3 Lysine 4 Methylation^*

Pierre-Marie Dehé, Bernhard Dichtl, Daniel Schaft^¶, Assen Roguev^¶, Mercè Pamblanco^||, Régine Lebrun, Alfonso Rodríguez-Gil^**, Msau Mkandawire^¶, Katarina Landsberg^¶, Anna Shevchenko, Andrej Shevchenko, Lorena E. Rosaleny^||, Vicente Tordera^||1, Sebastián Chávez^**2, A. Francis Stewart^¶3, and Vincent Géli⁴

From the Laboratoire d'InstabilitéduGénome et Cancérogénèse, Institut de Biologie Structurale et Microbiologie, CNRS, Marseille 13402, France, Institute of Molecular Biology, University of Zürich, Zürich CH-8057, Switzerland, ^¶Genomics, Biotec Research Centre, Technische Universitaet Dresden, Dresden 01307, Germany, Max-Planck Institute of Molecular Cell Biology and Genetics, Dresden 01307, Germany, ^||Departament de Bioquimica i Biologia Molecular, Universitat de València, Burjassot 46100, Spain, and ^**Departamento de Genética, Facultad de Biologia, Universidad de Sevilla, Sevilla 41012, Spain

Set1 is the catalytic subunit and the central component of the evolutionarily conserved Set1 complex (Set1C) that methylates histone 3 lysine 4 (H3K4). Here we have determined protein/protein interactions within the complex and related the substructure to function. The loss of individual Set1C subunits differentially affects Set1 stability, complex integrity, global H3K4 methylation, and distribution of H3K4 methylation along active genes. The complex requires Set1, Swd1, and Swd3 for integrity, and Set1 amount is greatly reduced in the absence of the Swd1-Swd3 heterodimer. Bre2 and Sdc1 also form a heteromeric subunit, which requires the SET domain for interaction with the complex, and Sdc1 strongly interacts with itself. Inactivation of either Bre2 or Sdc1 has very similar effects. Neither is required for complex integrity, and their removal results in an increase of H3K4 mono- and dimethylation and a severe decrease of trimethylation at the 5' end of active coding regions but a decrease of H3K4 dimethylation at the 3' end of coding regions. Cells lacking Spp1 have a reduced amount of Set1 and retain a fraction of trimethylated H3K4, whereas cells lacking Shg1 show slightly elevated levels of both di- and trimethylation. Set1C associates with both serine 5- and serine 2-phosphorylated forms of polymerase II, indicating that the association persists to the 3' end of transcribed genes. Taken together, our results suggest that Set1C subunits stimulate Set1 catalytic activity all along active genes.

Received for publication, March 31, 2006 , and in revised form, August 18, 2006.

^* This work was supported in part by the Acciones Integradas Hispano-Francesas (HF2003-0170) and the "Picasso Program". The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by Grant BFU2005-02603 from the Ministerio de Educación y Ciencia, Spain.

² Supported by the Ministerio de Ciencia y Tecnología (Grant BMC2003-07072-C03-01) and Instituto de Salud Carlos III (Grant 02/1363).

³ To whom correspondence may be addressed: Biotec Research Centre, Technische Universitaet Dresden, BioInnovationsZentrum, Am Tatzberg 47, 01307 Dresden, Germany. Tel.: 49-351-46340129; Fax: 49-351-46340143; E-mail: stewart{at}biotec.tu-dresden.de.

⁴ Supported by "La Ligue contre le cancer" (équipe labellisée). To whom correspondence may be addressed: InstabilitéduGénome et Cancérogénèse, Institut de Structurale et Microbiologie, CNRS, 31 chemin Joseph Aiguier, 13402, Marseille cedex 20, France. Tel.: 33-491-164-532; Fax: 33-491-712-124; E-mail: geli{at}ibsm.cnrs-mrs.fr.

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