Implications of polyadenylation in health and disease

Abstract

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.

Dynamic landscape of alternative polyadenylation during retinal development

“…The RNA-binding proteins (RBPs) and/or microRNAs (miRNAs) have been reported to interact with cis-regulatory elements in 3′UTRs, and the gain/loss of these elements during the change of 3′UTR length is related with RNA stability and/or translation efficiency [2, 3, 11, 20–23]. To examine possible involvement of RBPs and miRNAs in regulating gene expression, the binding motifs of RBPs and miRNAs were searched against the lengthened/shortened regions of 3′UTRs introduced by alternative usage of the distal PAS (see Methods for details).…”

“…3′UTRs often harbor various regulatory sequences, including the target sites of trans-acting factors, such as RNA-binding proteins (RBPs) [10, 16, 17] and microRNAs (miRNAs) [18, 19]. The gain/loss of the cis-acting elements in the 3′UTR isoforms caused by APA, can affect not only the stability but also the localization, transport and translational properties of the mRNA [2, 3, 11, 20–23], thereby contributing to functional diversity and gene regulation.…”

“…In addition, altered RNA polyadenylation has been associated with numerous neurological, immunological, oncological, hematological, and endocrine disorders [11, 12, 20, 27]. For instance, myotonic dystrophy is characterized by disruption of developmentally regulated APA events as a result of diminished MBNL activity due to sequestration by microsatellite expansion RNAs [28, 29].…”

The Nrd1-like protein Seb1 coordinates cotranscriptional 3′ end processing and polyadenylation site selection

“…S2F-H), suggesting that S. pombe Seb1 and S. cerevisiae Pcf11 contribute to different aspects of 3 ′ end processing. The importance of precisely selecting the correct poly (A) site is key during embryonic development and is of primordial importance for human health (Curinha et al 2014). The identification of Seb1 as an essential factor that can influence 3 ′ end processing decisions in a cotranscriptional manner is an important advance in understanding the interplay between transcription and APA regulation.…”

Is There Any Common Pathophysiology between Central Nervous System Lupus and Parkinson’s Disease?

“…Therefore, coincidence of Parkinson's disease and CNS lupus could be possible. Secondly, polyadenylation in ribonucleic acid (RNA) processing step may affect both Parkinson's disease and SLE [4]. Polyadenylation is important in messenger RNA stability and deficit in this process may lead to the development of diseases.…”