PDF(Pubmed)
Abstract：
Poly(ADP-ribosylation) (PARylation) is a post-translational modification mediated by a subset of ADP-ribosyl transferases (ARTs). Although PARylation-inhibition based therapies are considered as an avenue to combat debilitating diseases such as cancer and myopathies, the role of this modification in physiological processes such as cell differentiation remains unclear. Here, we show that Tankyrase1 (TNKS1), a PARylating ART, plays a major role in myogenesis, a vital process known to drive muscle fiber formation and regeneration. Although all bona fide PARPs are expressed in muscle cells, experiments using siRNA-mediated knockdown or pharmacological inhibition show that TNKS1 is the enzyme responsible of catalyzing PARylation during myogenesis. Via this activity, TNKS1 controls the turnover of mRNAs encoding myogenic regulatory factors such as nucleophosmin (NPM) and myogenin. TNKS1 mediates these effects by targeting RNA-binding proteins such as Human Antigen R (HuR). HuR harbors a conserved TNKS-binding motif (TBM), the mutation of which not only prevents the association of HuR with TNKS1 and its PARylation, but also precludes HuR from regulating the turnover of NPM and myogenin mRNAs as well as from promoting myogenesis. Therefore, our data uncover a new role for TNKS1 as a key modulator of RBP-mediated post-transcriptional events required for vital processes such as myogenesis.
摘要：
聚(ADP-核糖基化)(PARylation)是由ADP-核基转移酶(ART)的子集介导的翻译后修饰。尽管基于PARylation抑制的疗法被认为是对抗癌症和肌病等衰弱疾病的途径，这种修饰在细胞分化等生理过程中的作用尚不清楚。这里,我们证明了Tankyrase1(TNKS1)，PARylating艺术，在肌生成中起主要作用，已知驱动肌肉纤维形成和再生的重要过程。尽管所有真正的PARP都在肌肉细胞中表达，使用siRNA介导的敲减或药理学抑制的实验表明，TNKS1是负责在肌生成过程中催化PARylation的酶。通过这次活动,TNKS1控制编码生肌调节因子如核磷蛋白(NPM)和肌原蛋白的mRNA的周转。TNKS1通过靶向RNA结合蛋白如人抗原R(HuR)来介导这些作用。HuR具有保守的TNKS结合基序（TBM），其突变不仅阻止了HuR与TNKS1及其PARA化的关联，但也阻止了HuR调节NPM和肌原蛋白mRNA的周转以及促进肌生成。因此,我们的数据揭示了TNKS1作为RBP介导的转录后事件的关键调节因子的新作用,这些转录后事件是重要过程所必需的,如肌肉发生.
