PARN deadenylase is involved in miRNA-dependent degradation of TP53 mRNA in mammalian cells.
PARN deadenylase is involved in miRNA-dependent degradation of TP53 mRNA in mammalian cells.
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DOI：
10.1093/nar/gkv959
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发表时间：
2015-12-15
影响因子：
14.9
通讯作者：
Kleiman FE
中科院分区：
文献类型：
--
作者：
Zhang X;Devany E;Murphy MR;Glazman G;Persaud M;Kleiman FE
真核生物mRNA的失腺苷酸化受顺式作用调控元件控制，包括富含AU的元件（ARE）和microRNA（miRNA）靶向位点，位于真核生物mRNA的3 ′非翻译区（3 ′ UTRs）。脱腺苷酸酶通过与miRNA诱导的沉默复合物（miRISC）相互作用促进miRNA诱导的mRNA衰减。然而，poly（A）特异性核糖核酸酶（PARN）去腺苷酸酶在miRNA依赖性mRNA降解中的作用尚未阐明。在这里，我们提出的证据表明，不仅ARE，而且miRNA介导的途径参与PARN介导的TP53 mRNA的稳态水平的调节，它编码的肿瘤抑制基因p53。支持这一点，Argonaute-2（Ago-2），miRISC的核心组分，可以与PARN共存于复合物中，导致其去腺苷酶活性的激活。PARN不仅通过ARE调控TP53 mRNA的稳定性，还通过3 ′ UTR中相邻的miR-504/miR-125 b靶向位点调控TP53 mRNA的稳定性。更重要的是，我们发现miR-125b负载的miRISC有助于PARN特异性募集到TP53 mRNA，并且可以被ARE结合蛋白HuR逆转。总之，我们的研究为PARN在mRNA衰减的miRNA依赖性控制中的作用以及p53表达调控背后的机制提供了新的见解。
mRNA deadenylation is under the control of cis-acting regulatory elements, which include AU-rich elements (AREs) and microRNA (miRNA) targeting sites, within the 3′ untranslated region (3′ UTRs) of eukaryotic mRNAs. Deadenylases promote miRNA-induced mRNA decay through their interaction with miRNA-induced silencing complex (miRISC). However, the role of poly(A) specific ribonuclease (PARN) deadenylase in miRNA-dependent mRNA degradation has not been elucidated. Here, we present evidence that not only ARE- but also miRNA-mediated pathways are involved in PARN-mediated regulation of the steady state levels of TP53 mRNA, which encodes the tumor suppressor p53. Supporting this, Argonaute-2 (Ago-2), the core component of miRISC, can coexist in complexes with PARN resulting in the activation of its deadenylase activity. PARN regulates TP53 mRNA stability through not only an ARE but also an adjacent miR-504/miR-125b-targeting site in the 3′ UTR. More importantly, we found that miR-125b-loaded miRISC contributes to the specific recruitment of PARN to TP53 mRNA, and that can be reverted by the ARE-binding protein HuR. Together, our studies provide new insights into the role of PARN in miRNA-dependent control of mRNA decay and into the mechanisms behind the regulation of p53 expression.