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

Author:

Avendaño-Vázquez S. Eréndira,Dhir Ashish,Bembich Sara,Buratti Emanuele,Proudfoot Nicholas,Baralle Francisco E.

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.

Publisher

Cold Spring Harbor Laboratory

Subject

Developmental Biology,Genetics

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