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

被引：139

作者：

Avendano-Vazquez, S. Erendira ^{[2
]}

Dhir, Ashish ^{[1
]}

Bembich, Sara ^{[2
]}

Buratti, Emanuele ^{[2
]}

Proudfoot, Nicholas ^{[1
]}

Baralle, Francisco E. ^{[2
]}

机构：

[1] Univ Oxford, Sir William Dunn Sch Pathol, Oxford OX1 3RE, England

[2] Int Ctr Genet Engn & Biotechnol, I-34149 Trieste, Italy

来源：

GENES & DEVELOPMENT | 2012年 / 26卷 / 15期

基金：

英国惠康基金;

关键词：

ALS; FTD; TDP-43; autoregulation; mRNA splicing; polyadenylation; FRONTOTEMPORAL LOBAR DEGENERATION; AMYOTROPHIC-LATERAL-SCLEROSIS; GENE-EXPRESSION; TRANSGENIC MICE; POLYMERASE-II; POLYADENYLATION; DECAY; PHOSPHORYLATION; PROTEINOPATHY; ACCUMULATION;

D O I：

10.1101/gad.194829.112

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：1679 / 1684

页数：6

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