Autoregulation of TDP-43 mRNA levels involves interplay between transcription, splicing, and alternative polyA site selection
- S. Eréndira Avendaño-Vázquez1,3,
- Ashish Dhir2,3,
- Sara Bembich1,3,
- Emanuele Buratti1,
- Nicholas Proudfoot2,4 and
- Francisco E. Baralle1,4
- 1International Centre for Genetic Engineering and Biotechnology, 34149 Trieste, Italy;
- 2Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, United Kingdom
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↵3 These authors contributed equally to this work.
Abstract
TDP-43 is a critical RNA-binding factor associated with pre-mRNA splicing in mammals. Its expression is tightly autoregulated, with loss of this regulation implicated in human neuropathology. We demonstrate that TDP-43 overexpression in humans and mice activates a 3′ untranslated region (UTR) intron, resulting in excision of the proximal polyA site (PAS) pA1. This activates a cryptic PAS that prevents TDP-43 expression through a nuclear retention mechanism. Superimposed on this process, overexpression of TDP-43 blocks recognition of pA1 by competing with CstF-64 for PAS binding. Overall, we uncover complex interplay between transcription, splicing, and 3′ end processing to effect autoregulation of TDP-43.
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Footnotes
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↵4 Corresponding authors
E-mail baralle{at}icgeb.org
E-mail nicholas.proudfoot{at}path.ox.ac.uk
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Supplemental material is available for this article.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.194829.112.
- Received April 24, 2012.
- Accepted June 21, 2012.
- Copyright © 2012 by Cold Spring Harbor Laboratory Press
Freely available online through the Genes & Development Open Access option.