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J. Biol. Chem., Vol. 280, Issue 34, 30619-30629, August 26, 2005

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Transcription-dependent Association of Multiple Positive Transcription Elongation Factor Units to a HEXIM Multimer^*

Cyprien Dulac, Annemieke A. Michels, Alessandro Fraldi¶||, François Bonnet, Van Trung Nguyen, Giuliana Napolitano¶, Luigi Lania¶, and Olivier Bensaude**

From the Unite Mixte de Recherche 8541 CNRS, Ecole Normale Supérieure, Laboratoire de Régulation de l'Expression Génétique, 75230 Paris Cedex 05, France and ^¶Dipartimento di Biologia Strutturale e Funzionale, Università di Napoli Federico II, 80134 Napoli, Italy

The positive transcription elongation factor (P-TEFb) comprises a kinase, CDK9, and a Cyclin T1 or T2. Its activity is inhibited by association with the HEXIM1 or HEXIM2 protein bound to 7SK small nuclear RNA. HEXIM1 and HEXIM2 were found to form stable homo- and hetero-oligomers. Using yeast two-hybrid and transfection assays, we have now shown that the C-terminal domains of HEXIM proteins directly interact with each other. Hydrodynamic parameters measured by glycerol gradient ultracentrifugation and gel-permeation chromatography demonstrate that both purified recombinant and cellular HEXIM1 proteins form highly anisotropic particles. Chemical cross-links suggest that HEXIM1 proteins form dimers. The multimeric nature of HEXIM1 is maintained in P-TEFb·HEXIM1·7SK RNA complexes. Multiple P-TEFb modules are found in the inactive P-TEFb·HEXIM1·7SK complexes. It is proposed that 7SK RNA binding to a HEXIM1 multimer promotes the simultaneous recruitment and hence inactivation of multiple P-TEFb units.

Received for publication, March 7, 2005 , and in revised form, June 24, 2005.

^* This work was supported by grants from the Association pour la Recherche sur le Cancer, Action Concertée et Incitative Biologie Moléculaire et Structurale, and Agence Nationale de Recherche sur le SIDA (to O. B. and C. D.), a Sidaction fellowship (to A. A. M.), a European Molecular Biology Organization short-term fellowship (to A. F.), and the National Research Program on AIDS, Associazone Italiana per la Ricerca sul Cancro (to L. L.). 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.

Both authors made equal contributions to this work.

^|| Present address: Telethon Institute of Genetics and Medicine, Via P. Castellino 111, 80131 Napoli, Italy.

^** To whom correspondence should be addressed: Unite Mixte de Recherche 8541 CNRS, Ecole Normale Supérieure, Laboratoire de Régulation de l'Expression Génétique, 46 rue d'Ulm, 75230 Paris Cedex 05, France. Tel.: 33-1-4432-3410; Fax: 33-1-4432-3941; E-mail: bensaude{at}biologie.ens.fr.

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