Molecular Cell
Volume 55, Issue 2, 17 July 2014, Pages 186-198
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Article
Direct Binding of Ataxin-2 to Distinct Elements in 3′ UTRs Promotes mRNA Stability and Protein Expression

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Highlights

  • Ataxin-2 binds directly to RNAs in a PABPC1-independent manner in vivo

  • Ataxin-2 predominantly targets U-rich elements present within the 3′ UTRs of mRNAs

  • Direct binding of Ataxin-2 promotes mRNA stability and protein expression

  • Disease-associated polyglutamine expansion downregulates the activity of Ataxin-2

Summary

It has been proposed that Ataxin-2, a member of the like-Sm (LSm) protein family, participates in the regulation of RNA metabolism through interaction with PABPC1. However, the exact biological mechanism and in vivo targets remain unknown. Here, we report that Ataxin-2 binds directly to RNAs in a PABPC1-independent manner. High-throughput sequencing of Ataxin-2-bound RNAs prepared by PAR-CLIP revealed that Ataxin-2 binds predominantly to uridine-rich elements, including well-characterized cis-regulatory AU-rich elements, in the 3′ UTRs of target mRNAs. Gene expression analysis after Ataxin-2 depletion or overexpression revealed that Ataxin-2 stabilizes target mRNAs and increases the abundance of the corresponding proteins. A tethering assay demonstrated that Ataxin-2 elicits this effect by direct interaction with mRNAs. We also found that disease-associated polyglutamine expansion downregulates the physiological activity of Ataxin-2. These findings suggest that Ataxin-2 is an RNA-binding protein that targets cis-regulatory elements in 3′ UTRs to stabilize a subset of mRNAs and increase protein expression.

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