Format

Send to

Choose Destination
Nucleus. 2014;5(6):508-19. doi: 10.4161/nucl.36360. Epub 2014 Oct 31.

Implications of polyadenylation in health and disease.

Author information

1
a Gene Regulation Group; IBMC-Instituto de Biologia Molecular e Celular ; Universidade do Porto ; Porto , Portugal.

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.

KEYWORDS:

3′ untranslated region; 3′READS, 3′ Region Extraction and Deep Sequencing; AD, Alzheimer disease; APA, Alternative polyadenylation; AREs, Au-rich elements; BPV, bovine papilloma virus; CAH, congenital adrenal hyperplasia; CFIm25, Cleavage Factor Im 25 kDa; COX-2, cyclooxygenase 2; CPSF, Cleavage and Polyadenylation Specificity Factor; CSTF2, cleavage stimulatory factor-64kDa; DMKN, dermokine; DSE, downstream sequence element; ESC, embryonic stem cells; FMR1, Fragil X mental retardation 1; FOXP3, forkhead box P3; FXPOI, fragile X-associated immature ovarian insufficiency; FXS, Fragile X syndrome; FXTAS, fragile X-associated tremor/ataxia syndrome; HGRG-14, high-glucose-regulated gene; IMP-1, Insulin-like growth factor 2 mRNA binding protein 1; IPEX, immune dysfunction, polyendocrinopathy, enteropathy, X-linked; LPS, lipopolysaccharide; OPMD, oculopharyngeal muscular dystrophy; PABPN1, poly(A) binding protein; PAP, polyA polymerase; PAS, polyA site; PD, Parkinson disease; PDXK, pyridoxal kinase; PPIE, peptidylpropylisomerase E; RBP, RNA-binding protein; RNA Pol II, RNA polymerase II; SLE, systemic lupus erythematosus; SMA, Spinal Muscular Atrophy; SMN, Survival Motor Neuron; SNP, single nucleotide polymorphism; StAR, steroigogenic acute regulatory; TCF/LEF, T cell factor/lymphoid enhancer factor.; TCF7L2, transcription factor 7-like 2; TCR, T cell receptor; TLI, tandem UTR length index; TNF-α, tumor necrosis factor-α; USE, upstream sequence element; UTR, untranslated region; WAS, Wiskott-Aldrich syndrome; WASP, Wiskott-Aldrich syndrome protein; aSyn, α-Synuclein; aSynL, longest aSyn isoform; alternative polyadenylation; cell state; disease; gene expression; miRNA, microRNA; nuclear 1; pA signal, polyA signal; pA tail, polyA tail; polyadenylation; siRNAs, small interfering RNAs; snRNPs, spliceosomal small nuclear ribonucleoproteins; α-GalA, α-galactosidase A; μ, IgM heavy-chain mRNA

PMID:
25484187
PMCID:
PMC4615197
DOI:
10.4161/nucl.36360
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Taylor & Francis Icon for PubMed Central
Loading ...
Support Center