Recruitment and activation of mRNA decay enzymes by two ARE-mediated decay activation domains in the proteins TTP and BRF-1

• Published in: Genes & development Vol. 19; no. 3; pp. 351 - 361
• Main Authors: Lykke-Andersen, Jens, Wagner, Eileen
• Format: Journal Article
• Language: English
• Published: United States Cold Spring Harbor Laboratory Press 01.02.2005
• Subjects: Butyrate Response Factor 1; DNA-Binding Proteins - metabolism; Endoribonucleases - metabolism; Humans; Immediate-Early Proteins - metabolism; Protein Structure, Tertiary; Research Papers; Ribonucleases - metabolism; RNA, Messenger - metabolism; TATA-Binding Protein Associated Factors - metabolism; Tristetraprolin
• ISSN: 0890-9369; 1549-5477
• DOI: 10.1101/gad.1282305

In human cells, a critical pathway in gene regulation subjects mRNAs with AU-rich elements (AREs) to rapid decay by a poorly understood process. AREs have been shown to directly activate deadenylation, decapping, or 3′-to-5′ exonucleolytic decay. We demonstrate that enzymes involved in all three of these mRNA decay processes, as well as 5′-to-3′ exonucleolytic decay, associate with the protein tristetraprolin (TTP) and its homolog BRF-1, which bind AREs and activate mRNA decay. TTP and BRF-1 each contain two activation domains that can activate mRNA decay after fusion to a heterologous RNA-binding protein, and inhibit ARE-mediated mRNA decay when overexpressed. Both activation domains employ trans -acting factors to trigger mRNA decay, and the N-terminal activation domain functions as a binding platform for mRNA decay enzymes. Our data suggest that the TTP protein family functions as a molecular link between ARE-containing mRNAs and the mRNA decay machinery by recruitment of mRNA decay enzymes, and help explain how deadenylation, decapping, and exonucleolytic decay can all be independently activated on ARE-containing mRNAs. This describes a potentially regulated step in activation of mRNA decay.