TDP-43 mRNA 水平的自动调节涉及转录、剪接和选择性 polyA 位点选择之间的相互作用。
Autoregulation of TDP-43 mRNA levels involves interplay between transcription, splicing, and alternative polyA site selection.
机构信息
International Centre for Genetic Engineering and Biotechnology, Trieste, Italy.
出版信息
Genes Dev. 2012 Aug 1;26(15):1679-84. doi: 10.1101/gad.194829.112.
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.
摘要
TDP-43 是一种与哺乳动物前体 mRNA 剪接相关的关键 RNA 结合因子。其表达受到严格的自身调控，这种调控的丧失与人类神经病理学有关。我们证明，人类和小鼠中 TDP-43 的过表达会激活 3'非翻译区 (UTR) 内含子，导致近端 polyA 位点 (PAS) pA(1) 的切除。这激活了一个隐蔽的 PAS，通过核滞留机制阻止 TDP-43 的表达。在这个过程之上，TDP-43 的过表达通过与 CstF-64 竞争 PAS 结合来阻止 pA(1)的识别。总的来说，我们揭示了转录、剪接和 3' 端加工之间的复杂相互作用，以实现 TDP-43 的自身调控。
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