Department of Biochemistry and Biotechnology, University of Thessaly, Larissa, Greece.
Curr Med Chem. 2012;19(28):4838-49. doi: 10.2174/092986712803341539.
Deadenylation is the exoribonucleolytic shortening of eukaryotic poly(A) tails. It is often the first and rate-limiting step for mRNA decay and translational silencing. The process is catalysed by a diversity of deadenylases, which provide robust and flexible means to control mRNA levels and gene expression. Poly(A)-specific ribonuclease (PARN) is a major mammalian deadenylase and the only known to concurrently bind the 5' cap-structure and the 3' poly(A), thus enhancing the degradation rate and amplifying its processivity. PARN is important during oocyte maturation, embryogenesis, early development, DNA damage, and in cell-cycle progression, but also in processes beyond mRNA metabolism, such as the maturation of snoRNAs. The enzyme also participates in nonsense-mediated mRNA decay and in the regulation of cytoplasmic polyadenylation. Importantly, PARN is involved in the degradation of several cancer-related genes, while its expression is altered in cancer. Apart from the direct interaction with the cap structure, several strategies regulate PARN activity, such as phosphorylation, interaction with RNA-binding proteins (RBPs), and natural nucleotides. Recent studies have focused on the regulation of its activity by synthetic nucleoside analogues with therapeutic potential. In this context, the wide repertoire of RBPs and molecules that regulate PARN activity, together with the established role of deadenylases in miRNA-mediated regulation of mRNA expression, suggest that mRNA turnover is more complex than it was previously thought and PARN holds a key role in this process. In this review, we highlight the importance of PARN during RNA's lifecycle and discuss clinical perspectives of modulating its activity.
脱腺苷酸化是真核生物多聚（A）尾的外核核酸酶缩短。它通常是 mRNA 降解和翻译沉默的第一步和限速步骤。该过程由多种脱腺苷酸酶催化，这些酶为控制 mRNA 水平和基因表达提供了强大而灵活的手段。聚（A）特异性核糖核酸酶（PARN）是主要的哺乳动物脱腺苷酸酶，也是唯一已知的同时结合 5' 帽结构和 3' 多聚（A）的酶，从而提高了降解速率并放大了其进程。PARN 在卵母细胞成熟、胚胎发生、早期发育、DNA 损伤以及细胞周期进展中很重要，但在超越 mRNA 代谢的过程中也很重要，例如 snoRNA 的成熟。该酶还参与无意义介导的 mRNA 降解和细胞质多聚腺苷酸化的调节。重要的是，PARN 参与了几种与癌症相关基因的降解，而其表达在癌症中发生改变。除了与帽结构的直接相互作用外，几种策略调节 PARN 活性，例如磷酸化、与 RNA 结合蛋白（RBPs）的相互作用以及天然核苷酸。最近的研究集中在具有治疗潜力的合成核苷类似物对其活性的调节上。在这种情况下，广泛的 RBPs repertoire 和调节 PARN 活性的分子，以及脱腺苷酸酶在 miRNA 介导的 mRNA 表达调控中的既定作用，表明 mRNA 周转比以前想象的更为复杂，PARN 在该过程中起着关键作用。在这篇综述中，我们强调了 PARN 在 RNA 生命周期中的重要性，并讨论了调节其活性的临床观点。
