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A more recent version of this article appeared on November 1, 2002
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Submitted on March 21, 2002
Revised on June 18, 2002
Accepted on July 29, 2002
1 Department of Cell Biology and Genetics, Institute of Botany, University of Vienna, Rennweg 14, A-1030 Vienna
* Corresponding author. E-mail address: Michael.Jantsch{at}univie.ac.at.
The human RNA-editing enzyme ADAR1 is expressed in two versions. A longer, 150 kDa protein is interferon inducible and can be found both in the nucleus and cytoplasm. An aminoterminally truncated 110 kDa version, in contrast, is constitutively expressed and predominantly nuclear. In the absence of transcription, however, the shorter protein is also cytoplasmic and thus displays the hallmarks of a shuttling protein. The nuclear localization signal (NLS) of hsADAR1 is atypical and overlaps with its third double-stranded RNA-binding domain (dsRBD). Here we identify regions in hsADAR1 that interfere with nuclear localization and mediate cytoplasmic accumulation. We show that interferon inducible hsADAR1 contains a Crm1-dependent nuclear export signal in its aminoterminus. Most importantly, we demonstrate that the first dsRBD of hsADAR1 interferes with nuclear localization of a reporter construct containing dsRBD3 as an active NLS. The same effect can be triggered by several other, but not all dsRBDs. Active RNA-binding of either the inhibitory dsRBD1 or the NLS bearing dsRBD3 is required for cytoplasmic accumulation. Furthermore, hsADAR1's dsRBD1 has no effect on other NLSs suggesting RNA-mediated cross-talk between dsRBDs possibly leading to masking of the NLS. A model, incorporating these findings is presented. Finally, we identify a third region located in the C-terminus of hsADAR1 that also interferes with nuclear accumulation of this protein.
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