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Vol. 17, Issue 7, 3211-3220, July 2006

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Substrate-dependent Contribution of Double-stranded RNA-binding Motifs to ADAR2 Function

Ming Xu^*, K. Sam Wells, and Ronald B. Emeson^*,

Departments of *Pharmacology and Molecular Physiology and Biophysics, School of Medicine, Vanderbilt University, Nashville, TN 37232-8548

Submitted February 27, 2006; Revised March 31, 2006; Accepted April 21, 2006
Monitoring Editor: Weis Karsten

ADAR2 is a double-stranded RNA-specific adenosine deaminase involved in the editing of mammalian RNAs by the site-specific conversion of adenosine to inosine (A-to-I). ADAR2 contains two tandem double-stranded RNA-binding motifs (dsRBMs) that are not only important for efficient editing of RNA substrates but also necessary for localizing ADAR2 to nucleoli. The sequence and structural similarity of these motifs have raised questions regarding the role(s) that each dsRBM plays in ADAR2 function. Here, we demonstrate that the dsRBMs of ADAR2 differ in both their ability to modulate subnuclear localization as well as to promote site-selective A-to-I conversion. Surprisingly, dsRBM1 contributes to editing activity in a substrate-dependent manner, indicating that dsRBMs recognize distinct structural determinants in each RNA substrate. Although dsRBM2 is essential for the editing of all substrates examined, a point mutation in this motif affects editing for only a subset of RNAs, suggesting that dsRBM2 uses unique sets of amino acid(s) for functional interactions with different RNA targets. The dsRBMs of ADAR2 are interchangeable for subnuclear targeting, yet such motif alterations do not support site-selective editing, indicating that the unique binding preferences of each dsRBM differentially contribute to their pleiotropic function.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

Address correspondence to: Ronald Emeson ( ron.emeson{at}vanderbilt.edu)

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