| 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 (ŽECS) required for adenosine-to-inosine (A-to-I) conversion. Here we demonstrate that ADAR2 autoediting and subsequent alternative splicing are abolished in homozygous ŽECS 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.
|
| Files |
| Filename |
Size |
Approximate Download Time
(Hours:Minutes:Seconds)
|
| 28.8 Modem |
56K Modem |
ISDN (64 Kb) |
ISDN (128 Kb) |
Higher-speed Access |
| |
YiFengThesisDec022005.pdf |
5.32 Mb |
00:24:38 |
00:12:40 |
00:11:05 |
00:05:32 |
00:00:28 |
|
