title: Autoregulation of TDP-43 mRNA levels involves interplay between transcription, splicing, and alternative polyA site selection.
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.
authors.affiliation: International Centre for Genetic Engineering and Biotechnology, Trieste, Italy.
authors.forename: S Eréndira
authors.initials: SE
authors.lastname: Avendaño-Vázquez
authors.forename: Ashish
authors.initials: A
authors.lastname: Dhir
authors.forename: Sara
authors.initials: S
authors.lastname: Bembich
authors.forename: Emanuele
authors.initials: E
authors.lastname: Buratti
authors.forename: Nicholas
authors.initials: N
authors.lastname: Proudfoot
authors.forename: Francisco E
authors.initials: FE
authors.lastname: Baralle
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D039241:Cleavage Stimulation Factor / Q000737:chemistry / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D007438:Introns; D051379:Mice; D008969:Molecular Sequence Data; D011061:Poly A / Q000378:metabolism*; D011485:Protein Binding; D022821:RNA Splice Sites; D012326:RNA Splicing; D012333:RNA, Messenger / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: C474466:CSTF2T protein, human; D039241:Cleavage Stimulation Factor; C492658:Cstf2t protein, mouse; D004268:DNA-Binding Proteins; D022821:RNA Splice Sites; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D011061:Poly A