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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.

Original publication

DOI

10.1101/gad.194829.112

Type

Journal article

Journal

Genes Dev

Publication Date

01/08/2012

Volume

26

Pages

1679 - 1684

Keywords

Alternative Splicing, Animals, Base Sequence, Cell Line, Cleavage Stimulation Factor, DNA-Binding Proteins, Homeostasis, Humans, Introns, Mice, Molecular Sequence Data, Poly A, Protein Binding, RNA Splice Sites, RNA Splicing, RNA, Messenger, RNA-Binding Proteins, Transcription, Genetic