Abstract
The human transcriptome is highly dynamic, with each cell type, tissue, and organ system expressing an ensemble of transcript isoforms that give rise to considerable diversity. Apart from alternative splicing affecting the “body” of the transcripts, extensive transcriptome diversification occurs at the 3′ end. Transcripts differing at the 3′ end can have profound physiological effects by encoding proteins with distinct functions or regulatory properties or by affecting the mRNA fate via the inclusion or exclusion of regulatory elements (such as miRNA or protein binding sites). Importantly, the dynamic regulation at the 3′ end is associated with various (patho)physiological processes, including the immune regulation but also tumorigenesis. Here, we recapitulate the mechanisms of constitutive mRNA 3′ end processing and review the current understanding of the dynamically regulated diversity at the transcriptome 3′ end. We illustrate the medical importance by presenting examples that are associated with perturbations of this process and indicate resulting implications for molecular diagnostics as well as potentially arising novel therapeutic strategies.
Highlights
The mRNA and protein isoforms produced by alternative processing of primary RNA transcripts differ in structure, function, localization, or other properties [13, 120, 183]
The medical significance is highlighted by complex disorders that are associated with alternative cleavage and polyadenylation (APA), i.e., in the susceptibility to systemic lupus erythematosus [62] or more globally in tumorigenesis [119, 121]
There is some sequence flexibility [9, 173] and even alternative 3′ UTR architectures for effective processing [135], these findings indicate that the hexanucleotide required for recruitment of the CPSF complex represents the “Achilles heel” for disease causing loss-of-function mutations altering 3′ end processing
Summary
The mRNA and protein isoforms produced by alternative processing of primary RNA transcripts differ in structure, function, localization, or other properties [13, 120, 183]. A In influenza A virusinfected cells, the highly abundant NS1 protein interacts with the cellular 30 kDa subunit of CPSF and PABPN1 (not shown) [25] This prevents binding of the CPSF complex to its RNA substrates and selectively inhibits 3′ end processing and nuclear export of host pre-mRNAs. In contrast, the 3′ terminal poly(A) sequence on viral mRNAs is produced by the viral transcriptase, which reiteratively copies a stretch of four to seven uridines in the virion RNA templates. Only one gene is affected, the physiological consequences of incorrect polo PAS choice are detrimental; transgenic flies lacking the distal poly(A) signal cannot produce the longer transcript and die at the pupa stage due to a failure in the proliferation of the precursor cells of the abdomen [140] Along these lines transcription elongation factors can direct alternative RNA processing and thereby control important cellular functions such as the immunoglobulin secretion in plasma cells [117]. By means of the ongoing research elucidating how epigenetic modifications can control APA switches ([102, 182, 190] and references therein), it is tempting to speculate that the manipulation of these pathways may eventually be translated into the clinical context
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