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J. Biol. Chem., Vol. 282, Issue 24, 17649-17657, June 15, 2007

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Human TRBP and PACT Directly Interact with Each Other and Associate with Dicer to Facilitate the Production of Small Interfering RNA^*

Kin Hang Kok, Ming-Him James Ng, Yick-Pang Ching, and Dong-Yan Jin, A Leukemia and Lymphoma Society Scholar¹

From the Departments of Biochemistry and Anatomy, University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong, China

Mammalian Dicer interacts with double-stranded RNA-binding protein TRBP or PACT to mediate RNA interference and micro-RNA processing. TRBP and PACT are structurally related but exert opposite regulatory activities on PKR. It is not understood whether TRBP and PACT are simultaneously required for Dicer. Here we show that TRBP directly interacts with PACT in vitro and in mammalian cells. TRBP and PACT form a triple complex with Dicer and facilitate the production of small interfering RNA (siRNA) by Dicer. Knockdown of both TRBP and PACT in cultured cells leads to significant inhibition of gene silencing mediated by short hairpin RNA but not by siRNA, suggesting that TRBP and PACT function primarily at the step of siRNA production. Taken together, these findings indicate that human TRBP and PACT directly interact with each other and associate with Dicer to stimulate the cleavage of double-stranded or short hairpin RNA to siRNA. Our work significantly alters the current model for the assembly and function of the Dicer-containing complex that generates siRNA and micro-RNA in human.

Received for publication, December 22, 2006 , and in revised form, March 27, 2007.

^* This work was supported by Grants HKU 7683/05M and HKU1/06C from Hong Kong Research Grants Council, Grant AoE/M-04/04 from the University Grants Committee of Hong Kong, and a grant from Government Matching Grant Scheme (2005–2006) of Hong Kong. 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 To whom correspondence should be addressed: Dept. of Biochemistry, University of Hong Kong, 3/F Laboratory Block, Faculty of Medicine Bldg., 21 Sassoon Rd., Pokfulam, Hong Kong. Tel.: 852-2819-9491; Fax: 852-2855-1254; E-mail: dyjin{at}hkucc.hku.hk.

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