Curinha Ana, Oliveira Braz Sandra, Pereira-Castro Isabel, Cruz Andrea, Moreira Alexandra
a Gene Regulation Group; IBMC-Instituto de Biologia Molecular e Celular ; Universidade do Porto ; Porto , Portugal.
Nucleus. 2014;5(6):508-19. doi: 10.4161/nucl.36360. Epub 2014 Oct 31.
Polyadenylation is the RNA processing step that completes the maturation of nearly all eukaryotic mRNAs. It is a two-step nuclear process that involves an endonucleolytic cleavage of the pre-mRNA at the 3'-end and the polymerization of a polyadenosine (polyA) tail, which is fundamental for mRNA stability, nuclear export and efficient translation during development. The core molecular machinery responsible for the definition of a polyA site includes several recognition, cleavage and polyadenylation factors that identify and act on a given polyA signal present in a pre-mRNA, usually an AAUAAA hexamer or similar sequence. This mechanism is tightly regulated by other cis-acting elements and trans-acting factors, and its misregulation can cause inefficient gene expression and may ultimately lead to disease. The majority of genes generate multiple mRNAs as a result of alternative polyadenylation in the 3'-untranslated region. The variable lengths of the 3' untranslated regions created by alternative polyadenylation are a recognizable target for differential regulation and clearly affect the fate of the transcript, ultimately modulating the expression of the gene. Over the past few years, several studies have highlighted the importance of polyadenylation and alternative polyadenylation in gene expression and their impact in a variety of physiological conditions, as well as in several illnesses. Abnormalities in the 3'-end processing mechanisms thus represent a common feature among many oncological, immunological, neurological and hematological disorders, but slight imbalances can lead to the natural establishment of a specific cellular state. This review addresses the key steps of polyadenylation and alternative polyadenylation in different cellular conditions and diseases focusing on the molecular effectors that ensure a faultless pre-mRNA 3' end formation.
聚腺苷酸化是RNA加工步骤，它使几乎所有真核生物mRNA完成成熟。这是一个两步的核过程，包括前体mRNA在3'端的内切核酸酶切割和聚腺苷酸（polyA）尾巴的聚合，这对于mRNA稳定性、核输出以及发育过程中的高效翻译至关重要。负责定义聚腺苷酸位点的核心分子机制包括几个识别、切割和聚腺苷酸化因子，它们识别并作用于前体mRNA中存在的特定聚腺苷酸信号，通常是AAUAAA六聚体或类似序列。这种机制受到其他顺式作用元件和反式作用因子的严格调控，其失调会导致基因表达效率低下，并最终可能导致疾病。由于3'非翻译区的可变聚腺苷酸化，大多数基因会产生多种mRNA。可变聚腺苷酸化产生的3'非翻译区的不同长度是差异调控的一个可识别靶点，明显影响转录本的命运，最终调节基因的表达。在过去几年中，多项研究强调了聚腺苷酸化和可变聚腺苷酸化在基因表达中的重要性及其在多种生理条件以及几种疾病中的影响。因此，3'端加工机制异常是许多肿瘤、免疫、神经和血液疾病的共同特征，但轻微失衡可能导致特定细胞状态的自然形成。本综述探讨了不同细胞条件和疾病中聚腺苷酸化和可变聚腺苷酸化的关键步骤，重点关注确保前体mRNA 3'端完美形成的分子效应器。
