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Title page for ETD etd-12022005-143821


Type of Document Dissertation
Author Feng, Yi
Author's Email Address yi.feng@vanderbilt.edu
URN etd-12022005-143821
Title Autoregulation of ADAR2 function by RNA editing.
Degree PhD
Department Pharmacology
Advisory Committee
Advisor Name Title
Elaine Sanders-Bush Committee Chair
Heidi Hamm Committee Member
John Exton Committee Member
Steven Hanks Committee Member
Keywords
  • RNA editing
  • ADAR2
  • mouse
  • alternative splicing
  • autoregulation
  • gene expression
  • Adenosine deaminase
Date of Defense 2005-11-22
Availability unrestricted
Abstract
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 non-canonical adenosine-inosine (A-I) 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 (ƒŽECS) required for adenosine-to-inosine (A-to-I) conversion. Here we demonstrate that ADAR2 autoediting and subsequent alternative splicing are abolished in homozygous ƒŽECS mice and that ADAR2 protein expression is increased in numerous tissues when compared to wild-type animals. The observed increases in ADAR2 protein expression correlate with the extent of ADAR2 autoediting observed in 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.
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