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Molecular and Cellular Biology, October 2007, p. 6806-6817, Vol. 27, No. 19
0270-7306/07/$08.00+0     doi:10.1128/MCB.01036-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Elucidation of a C-Rich Signature Motif in Target mRNAs of RNA-Binding Protein TIAR{triangledown} ,{dagger}

Henry S. Kim,1,{ddagger} Yuki Kuwano,2,{ddagger} Ming Zhan,3 Rudolf Pullmann Jr.,2 Krystyna Mazan-Mamczarz,2 Huai Li,3 Nancy Kedersha,4 Paul Anderson,4 Matthew C. J. Wilce,1 Myriam Gorospe,2*,§ and Jacqueline A. Wilce1,§

Department of Biochemistry and Molecular Biology, Monash University, Victoria 3800, Australia,1 Laboratory of Cellular and Molecular Biology, National Institute on Aging-Intramural Research Program, National Institutes of Health, Baltimore, Maryland 21228,2 Research Resources Branch, National Institute on Aging-Intramural Research Program, National Institutes of Health, Baltimore, Maryland 21228,3 Division of Rheumatology and Immunology, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts 021154

Received 12 June 2007/ Returned for modification 10 July 2007/ Accepted 23 July 2007

The RNA-binding protein TIAR (related to TIA-1 [T-cell-restricted intracellular antigen 1]) was shown to associate with subsets of mRNAs bearing U-rich sequences in their 3' untranslated regions. TIAR can function as a translational repressor, particularly in response to cytotoxic agents. Using unstressed colon cancer cells, collections of mRNAs associated with TIAR were isolated by immunoprecipitation (IP) of (TIAR-RNA) ribonucleoprotein (RNP) complexes, identified by microarray analysis, and used to elucidate a common signature motif present among TIAR target transcripts. The predicted TIAR motif was an unexpectedly cytosine-rich, 28- to 32-nucleotide-long element forming a stem and a loop of variable size with an additional side loop. The ability of TIAR to bind an RNA oligonucleotide with a representative C-rich TIAR motif sequence was verified in vitro using surface plasmon resonance. By this analysis, TIAR containing two or three RNA recognition domains (TIAR12 and TIAR123) showed low but significant binding to the C-rich sequence. In vivo, insertion of the C-rich motif into a heterologous reporter strongly suppressed its translation in cultured cells. Using this signature motif, an additional ~2,209 UniGene targets were identified (2.0% of the total UniGene database). A subset of specific mRNAs were validated by RNP IP analysis. Interestingly, in response to treatment with short-wavelength UV light (UVC), a stress agent causing DNA damage, each of these target mRNAs bearing C-rich motifs dissociated from TIAR. In turn, expression of the encoded proteins was elevated in a TIAR-dependent manner. In sum, we report the identification of a C-rich signature motif present in TIAR target mRNAs whose association with TIAR decreases following exposure to a stress-causing agent.

* Corresponding author. Mailing address: Box 12, LCMB, NIA-IRP, NIH, 5600 Nathan Shock Dr., Baltimore, MD 21224. Phone: (410) 558-8443. Fax: (410) 558-8386. E-mail: myriam-gorospe{at}nih.gov

{triangledown} Published ahead of print on 6 August 2007.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} H.S.K. and Y.K. are co-first authors.

§ M.G. and J.A.W. are co-senior authors.

Molecular and Cellular Biology, October 2007, p. 6806-6817, Vol. 27, No. 19
0270-7306/07/$08.00+0     doi:10.1128/MCB.01036-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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