Department of Developmental Biology, Stanford University School of Medicine, Stanford, USA.
Escuela de Kinesiología, Facultad de Medicina y Ciencias de la Salud, Center for Integrative Biology (CIB), Universidad Mayor, Chile and Department of Neuroscience, Faculty of Medicine, Universidad de Chile, Santiago, Chile.
RNA Biol. 2023 Jan;20(1):908-925. doi: 10.1080/15476286.2023.2275109. Epub 2023 Oct 31.
Alternative processing of nascent mRNAs is widespread in eukaryotic organisms and greatly impacts the output of gene expression. Specifically, alternative cleavage and polyadenylation (APA) is a co-transcriptional molecular process that switches the polyadenylation site (PAS) at which a nascent mRNA is cleaved, resulting in mRNA isoforms with different 3'UTR length and content. APA can potentially affect mRNA translation efficiency, localization, stability, and mRNA seeded protein-protein interactions. APA naturally occurs during development and cellular differentiation, with around 70% of human genes displaying APA in particular tissues and cell types. For example, neurons tend to express mRNAs with long 3'UTRs due to preferential processing at PASs more distal than other PASs used in other cell types. In addition, changes in APA mark a variety of pathological states, including many types of cancer, in which mRNAs are preferentially cleaved at more proximal PASs, causing expression of mRNA isoforms with short 3'UTRs. Although APA has been widely reported, both the function of APA in development and the mechanisms that regulate the choice of 3'end cut sites in normal and pathogenic conditions are still poorly understood. In this review, we summarize current understanding of how APA is regulated during development and cellular differentiation and how the resulting change in 3'UTR content affects multiple aspects of gene expression. With APA being a widespread phenomenon, the advent of cutting-edge scientific techniques and the pressing need for studies, there has never been a better time to delve into the intricate mechanisms of alternative cleavage and polyadenylation.
非经典剪接和多聚腺苷酸化在真核生物中广泛存在，并极大地影响基因表达的输出。具体来说，可变剪接和多聚腺苷酸化（APA）是一种共转录的分子过程，它改变了新生 mRNA 的切割多聚腺苷酸化位点（PAS），导致具有不同 3'UTR 长度和内容的 mRNA 异构体。APA 可能会影响 mRNA 的翻译效率、定位、稳定性和 mRNA 引发的蛋白质-蛋白质相互作用。APA 自然发生在发育和细胞分化过程中，大约 70%的人类基因在特定组织和细胞类型中表现出 APA。例如，神经元倾向于表达具有长 3'UTR 的 mRNAs，因为在其他细胞类型中使用的其他 PAS 更远端的 PAS 处优先进行加工。此外，APA 的变化标志着多种病理状态，包括许多类型的癌症，其中 mRNAs 在更近端的 PAS 处优先切割，导致具有短 3'UTR 的 mRNA 异构体的表达。尽管 APA 已经被广泛报道，但 APA 在发育和正常及病理条件下调节 3'末端切割位点选择的机制及其功能仍知之甚少。在这篇综述中，我们总结了目前对 APA 如何在发育和细胞分化过程中受到调节的理解，以及 3'UTR 内容的变化如何影响基因表达的多个方面。由于 APA 是一种普遍现象，先进科学技术的出现以及对研究的迫切需求，现在正是深入研究可变剪接和多聚腺苷酸化的复杂机制的绝佳时机。
