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Molecular and Cellular Biology, January 2006, p. 480-488, Vol. 26, No. 2
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.2.480-488.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Altered RNA Editing in Mice Lacking ADAR2 Autoregulation§

Yi Feng,1,{dagger} Christopher L. Sansam,1,{dagger},{ddagger} Minati Singh,1 and Ronald B. Emeson1,2*

Departments of Pharmacology,1 Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-85482

Received 27 July 2005/ Returned for modification 23 August 2005/ Accepted 24 October 2005

ADAR2 is a double-stranded-RNA-specific adenosine deaminase involved in the editing of mammalian RNAs by the site-selective conversion of adenosine to inosine. Previous studies from our laboratory have demonstrated that ADAR2 can modify its own pre-mRNA to create a proximal 3' splice site containing a noncanonical adenosine-inosine dinucleotide. Alternative splicing to this proximal acceptor adds 47 nucleotides to the mature ADAR2 transcript, thereby resulting in the loss of functional ADAR2 protein expression due to premature translation termination in an alternate reading frame. To examine whether the editing of ADAR2 transcripts represents a negative autoregulatory strategy to modulate ADAR2 protein expression, we have generated genetically modified mice in which the ability of ADAR2 to edit its own pre-mRNA has been selectively ablated by deletion of a critical sequence (editing site complementary sequence [ECS]) required for adenosine-to-inosine conversion. Here we demonstrate that ADAR2 autoediting and subsequent alternative splicing are abolished in homozygous {Delta}ECS mice and that ADAR2 protein expression is increased in numerous tissues compared to wild-type animals. The observed increases in ADAR2 protein expression correlate with the extent of ADAR2 autoediting observed with wild-type tissues and correspond to increases in the editing of ADAR2 substrates, indicating that ADAR2 autoediting is a key regulator of ADAR2 protein expression and activity in vivo.

* Corresponding author. Mailing address: Department of Pharmacology, Vanderbilt University, 465 21st Avenue South, 8160 Medical Research Building 3, Nashville, TN 37232-8548. Phone: (615) 936-1688. Fax: (615) 936-1689. E-mail: ron.emeson{at}vanderbilt.edu.

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

{dagger} These authors contributed equally to this work.

{ddagger} Present address: MIT Center for Cancer Research, 400 Main Street, E15-524, Cambridge, MA 02139.

Molecular and Cellular Biology, January 2006, p. 480-488, Vol. 26, No. 2
0022-538X/06/$08.00+0     doi:10.1128/MCB.26.2.480-488.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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