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Global Analysis of Pub1p Targets Reveals a Coordinate Control of Gene Expression through Modulation of Binding and Stability

Radharani Duttagupta,^1,2 Bin Tian,³ Carol J. Wilusz,^1, Danny T. Khounh,¹ Patricia Soteropoulos,⁴ Ming Ouyang,⁵ Joseph P. Dougherty,^1* and Stuart W. Peltz¹

Department of Molecular Genetics, Microbiology, and Immunology,¹ The Graduate School of Biomedical Sciences, UMDNJ-Robert Wood Johnson Medical School, Piscataway, New Jersey 08854,² Department of Biochemistry and Molecular Biology, UMDNJ-New Jersey Medical School, Newark, New Jersey 07103,³ Center for Applied Genomics, Public Health Research Institute and Department of Microbiology and Molecular Genetics, UMDNJ-New Jersey Medical School, Newark, New Jersey 07103,⁴ Department of Pharmacology and Informatics Institute, UMDNJ-Robert Wood Johnson Medical School, Piscataway, New Jersey 08854⁵

Received 24 January 2005/ Returned for modification 2 March 2005/ Accepted 24 March 2005

Regulation of mRNA turnover is an important cellular strategy for posttranscriptional control of gene expression, mediated by the interplay of cis-acting sequences and associated trans-acting factors. Pub1p, an ELAV-like yeast RNA-binding protein with homology to T-cell internal antigen 1 (TIA-1)/TIA-1-related protein (TIAR), is an important modulator of the decay of two known classes of mRNA. Our goal in this study was to determine the range of mRNAs whose stability is dependent on Pub1p, as well as to identify specific transcripts that directly bind to this protein. We have examined global mRNA turnover in isogenic PUB1 and pub1 strains through gene expression analysis and demonstrate that 573 genes exhibit a significant reduction in half-life in a pub1 strain. We also examine the binding specificity of Pub1p using affinity purification followed by microarray analysis to comprehensively distinguish between direct and indirect targets and find that Pub1p significantly binds to 368 cellular transcripts. Among the Pub1p-associated mRNAs, 53 transcripts encoding proteins involved in ribosomal biogenesis and cellular metabolism are selectively destabilized in the pub1 strain. In contrast, genes involved in transporter activity demonstrate association with Pub1p but display no measurable changes in transcript stability. Characterization of two candidate genes, SEC53 and RPS16B, demonstrate that both Pub1p-dependent regulation of stability and Pub1p binding require 3' untranslated regions, which harbor distinct sequence motifs. These results suggest that Pub1p binds to discrete subsets of cellular transcripts and posttranscriptionally regulates their expression at multiple levels.

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

Present address: Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO 80523-1682.

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