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Terminal adenosyl transferase activity of posttranscriptional regulator HuR revealed by confocal on-bead screening

Meisner, Nicole-Claudia and Hintersteiner, Martin and Seifert, Jan-Marcus and Bauer, Roman and Benoit, Roger and Widmer, Armin and Schindler, Torsten and Uhl, Volker and Lang, Michaela and Gstach, Hubert and Auer, Manfred (2009) Terminal adenosyl transferase activity of posttranscriptional regulator HuR revealed by confocal on-bead screening. Journal of Molecular Biology, 386 (2). pp. 435-450. ISSN 1089-8638

Abstract

Posttranscriptional regulation and RNA metabolism have become central topics in the understanding of mammalian gene expression and cell signalling, with the 3' untranslated region emerging as the coordinating unit. The 3' untranslated region trans-acting factor Hu protein R (HuR) forms a central posttranscriptional pathway node bridging between AU-rich element-mediated processes and microRNA regulation. While (m)RNA control by HuR has been extensively characterized, the molecular mode of action still remains elusive. Here we describe the identification of the first RRM3 (RNA recognition motif 3) targeted low molecular weight HuR inhibitors from a one-bead-one-compound library screen using confocal nanoscanning. A further compound characterization revealed the presence of an ATP-binding pocket within HuR RRM3, associated with enzymatic activity. Centered around a metal-ion-coordinating DxD motif, the catalytic site mediates 3'-terminal adenosyl modification of non-polyadenylated RNA substrates by HuR. These findings suggest that HuR actively contributes to RNA modification and maturation and thereby shed an entirely new light on the role of HuR in RNA metabolism.

Item Type: Article
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Additional Information: Author can archive post-print (ie final draft post-refereeing); Publisher's version/PDF cannot be used
Keywords: HuR; AU-rich; posttranscriptional regulation; CONA; screening
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Date Deposited: 22 Feb 2010 11:50
Last Modified: 31 Jan 2013 00:52
URI: https://oak.novartis.com/id/eprint/1667

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