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Genes Dev. 2012 Aug 1;26(15):1679-84. doi: 10.1101/gad.194829.112.

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

Author information

1
International Centre for Genetic Engineering and Biotechnology, Trieste, Italy.

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) pA(1). 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 pA(1) 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.

PMID:
22855830
PMCID:
PMC3418585
DOI:
10.1101/gad.194829.112
[Indexed for MEDLINE]
Free PMC Article

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