Autoregulation of TDP-43 mRNA levels involves interplay between transcription, splicing, and alternative polyA site selection

  1. Francisco E. Baralle1,4
  1. 1International Centre for Genetic Engineering and Biotechnology, 34149 Trieste, Italy;
  2. 2Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, United Kingdom
    1. 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.

    Keywords

    Footnotes

    • Received April 24, 2012.
    • Accepted June 21, 2012.

    Freely available online through the Genes & Development Open Access option.

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