Journal
NUCLEUS
Volume 5, Issue 6, Pages 508-519Publisher
TAYLOR & FRANCIS INC
DOI: 10.4161/nucl.36360
Keywords
gene expression; polyadenylation; alternative polyadenylation; 3 untranslated region; disease; cell state; APA; Alternative polyadenylation; pA tail; polyA tail; PAP; polyA polymerase; PAS; polyA site; pA signal; polyA signal; UTR; untranslated region; miRNA; microRNA; RBP; RNA-binding protein; RNA Pol II; RNA polymerase II; TLI; tandem UTR length index; IMP-1; Insulin-like growth factor 2 mRNA binding protein 1; 3READS; 3 Region Extraction and Deep Sequencing; DMKN; dermokine; PDXK; pyridoxal kinase; PPIE; peptidylpropylisomerase E; CFIm25; Cleavage Factor Im 25kDa; IgM heavy-chain mRNA; CSTF2; cleavage stimulatory factor-64kDa; DSE; downstream sequence element; siRNAs; small interfering RNAs; TCR; T cell receptor; LPS; lipopolysaccharide; TNF-; tumor necrosis factor-; AREs; Au-rich elements; IPEX; immune dysfunction; polyendocrinopathy; enteropathy; X-linked; FOXP3; forkhead box P3; WAS; Wiskott-Aldrich syndrome; WASP; Wiskott-Aldrich syndrome protein; USE; upstream sequence element; CPSF; Cleavage and Polyadenylation Specificity Factor; ESC; embryonic stem cells; SLE; systemic lupus erythematosus; SNP; single nucleotide polymorphism; COX-2; cyclooxygenase 2; AD; Alzheimer disease; aSyn; -Synuclein; PD; Parkinson disease; aSynL; longest aSyn isoform; OPMD; oculopharyngeal muscular dystrophy; PABPN1; poly(A) binding protein; nuclear 1; -GalA; -galactosidase A; FMR1; Fragil X mental retardation 1; FXS; Fragile X syndrome; FXPOI; fragile X-associated immature ovarian insufficiency; FXTAS; fragile X-associated tremor; ataxia syndrome; snRNPs; spliceosomal small nuclear ribonucleoproteins; BPV; bovine papilloma virus; SMN; Survival Motor Neuron; SMA; Spinal Muscular Atrophy; StAR; steroigogenic acute regulatory; CAH; congenital adrenal hyperplasia; HGRG-14; high-glucose-regulated gene; TCF7L2; transcription factor 7-like 2; TCF; LEF; T cell factor; lymphoid enhancer factor
Categories
Funding
- FEDER through the Operational Competitiveness Programme-COMPETE
- National Funds through FCT (Fundacao para a Ciencia e a Tecnologia) [COMPETE: FCOMP-01-0124-FEDER-021201 (PTDC/SAU-GMG/116621/2010), FCOMP-01-0124-FEDER-028252 (PTDC/BEX-BCM/0468/2012), NORTE-07-0124-FEDER-000003]
- Programa Operacional Regional do Norte under the Quadro de Referencia Estrategico Nacional (QREN) [ON.2-O Novo Norte]
- Programa Operacional Regional do Norte through the Fundo Europeu de Desenvolvimento Regional (FEDER)
- FCT (Fundacao para a Ciencia e Tecnologia)
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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.
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