Journal
GENES & DEVELOPMENT
Volume 26, Issue 15, Pages 1679-1684Publisher
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.194829.112
Keywords
ALS; FTD; TDP-43; autoregulation; mRNA splicing; polyadenylation
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Funding
- AriSLA
- EMBO long-term fellowship
- Programme Grant from the Wellcome Trust
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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 39 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 39 end processing to effect autoregulation of TDP-43.
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