Emerging functions of alternative splicing coupled with nonsense-mediated decay

Hamid, Fursham; Makeyev, Eugene V.

doi:10.1042/bst20140066

Cited by 60 publications

(58 citation statements)

References 50 publications

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“…When we measure alternative splicing by high-throughput sequencing or RT-PCR, we are measuring the steady-state levels of the alternative isoforms, which are influenced both by the splicing machinery and the relative stability of the different isoforms. Alternative isoforms with differing stabilities are seen in the phenomenon of alternative splicing coupled to nonsense-mediated decay (AS-NMD) (Hamid and Makeyev 2014). NMD is triggered when a message contains a premature termination codon (PTC), and in AS-NMD, a change in reading frame at the alternative splice junction generates a PTC.…”

Section: Resultsmentioning

confidence: 99%

Coordinated tissue-specific regulation of adjacent alternative 3′ splice sites inC. elegans

et al. 2015

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Adjacent alternative 3′ splice sites, those separated by ≤18 nucleotides, provide a unique problem in the study of alternative splicing regulation; there is overlap of the cis-elements that define the adjacent sites. Identification of the intron's 3 ′ end depends upon sequence elements that define the branchpoint, polypyrimidine tract, and terminal AG dinucleotide. Starting with RNA-seq data from germline-enriched and somatic cell-enriched Caenorhabditis elegans samples, we identify hundreds of introns with adjacent alternative 3 ′ splice sites. We identify 203 events that undergo tissue-specific alternative splicing. For these, the regulation is monodirectional, with somatic cells preferring to splice at the distal 3 ′ splice site (furthest from the 5 ′ end of the intron) and germline cells showing a distinct shift toward usage of the adjacent proximal 3 ′ splice site (closer to the 5 ′ end of the intron). Splicing patterns in somatic cells follow C. elegans consensus rules of 3 ′ splice site definition; a short stretch of pyrimidines preceding an AG dinucleotide. Splicing in germline cells occurs at proximal 3 ′ splice sites that lack a preceding polypyrimidine tract, and in three instances the germline-specific site lacks the AG dinucleotide. We provide evidence that use of germline-specific proximal 3 ′ splice sites is conserved across Caenorhabditis species. We propose that there are differences between germline and somatic cells in the way that the basal splicing machinery functions to determine the intron terminus. [Supplemental material is available for this article.]Alternative splicing is a highly regulated process by which a cell can produce multiple messenger RNAs, potentially encoding multiple proteins, from a common precursor transcript. The de novo assembly of a spliceosome on each intron of a pre-mRNA transcript requires cis-elements within the intron that are recognized as signals marking the beginning, end, and branchpoint (Ares and Weiser 1995). A cassette exon is a form of alternative splicing in which an exon is either included or skipped in the mature mRNA. Conserved enhancer or silencer elements within the exon or the surrounding introns interact with an array of constitutive and tissue-specific trans-factors that promote or inhibit assembly of a functional spliceosome (Wang and Burge 2008). The use of alternative 3 ′ or 5 ′ splice sites modifies gene expression by including or skipping coding sequences at the ends of exons. Many examples of adjacent alternative 3 ′ splice sites, defined as being separated by 18 nucleotides (nt) or less, have been observed. In many species, a form of alternative 3 ′ splice site usage has been identified in which the alternative splicing acceptors are only 3 nt apart. Except for the rare example of AC dinucleotides observed for substrates of the minor spliceosome, introns end with AG dinucleotides. Alternative 3 ′ splice sites separated by only 3 nt are referred to as NAGNAGs, as the end of the intron consists of two AG splice acceptors separated by 3 nt. A...

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Section: Resultsmentioning

confidence: 99%

Coordinated tissue-specific regulation of adjacent alternative 3′ splice sites inC. elegans

et al. 2015

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“…These altered 3′-UTR boundaries often trigger rapid mRNP disassembly and mRNA degradation via the NMD pathway (see below) (74). In humans, several RBPs employ AS linked to NMD to regulate their own expression (75), or to cross-regulate expression of dozens of other RBPs (76). Furthermore, estimates suggest that nearly one-fifth (17–21%) of all AS events conserved between humans and mouse can alter 3′-UTR boundaries (77).…”

Section: The Mrnp Parts Listmentioning

confidence: 99%

The Clothes Make the mRNA: Past and Present Trends in mRNP Fashion

Singh

Pratt²,

Yeo³

et al. 2015

Annu. Rev. Biochem.

348

341

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Throughout their lifetimes, messenger RNAs (mRNAs) associate with proteins to form ribonucleoproteins (mRNPs). Since the discovery of the first mRNP component more than 40 years ago, what is known as the mRNA interactome now comprises >1,000 proteins. These proteins bind mRNAs in myriad ways with varying affinities and stoichiometries, with many assembling onto nascent RNAs in a highly ordered process during transcription and precursor mRNA (pre-mRNA) processing. The nonrandom distribution of major mRNP proteins observed in transcriptome-wide studies leads us to propose that mRNPs are organized into three major domains loosely corresponding to 5′ untranslated regions (UTRs), open reading frames, and 3′ UTRs. Moving from the nucleus to the cytoplasm, mRNPs undergo extensive remodeling as they are first acted upon by the nuclear pore complex and then by the ribosome. When not being actively translated, cytoplasmic mRNPs can assemble into large multi-mRNP assemblies or be permanently disassembled and degraded. In this review, we aim to give the reader a thorough understanding of past and current eukaryotic mRNP research.

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“…A prevalent post-transcriptional mechanism regulating mRNA abundance involves coupling between AS and nonsense-mediated decay (NMD), a quality control mechanism targeting mRNAs containing premature translation termination codons (PTCs) for degradation [17], [18]. AS-NMD plays important roles in diverse biological processes [19] including regulation of RNA-binding protein expression [20], [21], granulocyte development [22], axonal guidance [23] and brain response to seizures [24].…”

Section: Introductionmentioning

confidence: 99%

Regulation of mRNA Abundance by Polypyrimidine Tract-Binding Protein-Controlled Alternate 5′ Splice Site Choice

Hamid

Makeyev

2014

PLoS Genet

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Alternative splicing (AS) provides a potent mechanism for increasing protein diversity and modulating gene expression levels. How alternate splice sites are selected by the splicing machinery and how AS is integrated into gene regulation networks remain important questions of eukaryotic biology. Here we report that polypyrimidine tract-binding protein 1 (Ptbp1/PTB/hnRNP-I) controls alternate 5′ and 3′ splice site (5′ss and 3′ss) usage in a large set of mammalian transcripts. A top scoring event identified by our analysis was the choice between competing upstream and downstream 5′ss (u5′ss and d5′ss) in the exon 18 of the Hps1 gene. Hps1 is essential for proper biogenesis of lysosome-related organelles and loss of its function leads to a disease called type 1 Hermansky-Pudlak Syndrome (HPS). We show that Ptbp1 promotes preferential utilization of the u5′ss giving rise to stable mRNAs encoding a full-length Hps1 protein, whereas bias towards d5′ss triggered by Ptbp1 down-regulation generates transcripts susceptible to nonsense-mediated decay (NMD). We further demonstrate that Ptbp1 binds to pyrimidine-rich sequences between the u5′ss and d5′ss and activates the former site rather than repressing the latter. Consistent with this mechanism, u5′ss is intrinsically weaker than d5′ss, with a similar tendency observed for other genes with Ptbp1-induced u5′ss bias. Interestingly, the brain-enriched Ptbp1 paralog Ptbp2/nPTB/brPTB stimulated the u5′ss utilization but with a considerably lower efficiency than Ptbp1. This may account for the tight correlation between Hps1 with Ptbp1 expression levels observed across mammalian tissues. More generally, these data expand our understanding of AS regulation and uncover a post-transcriptional strategy ensuring co-expression of a subordinate gene with its master regulator through an AS-NMD tracking mechanism.

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Emerging functions of alternative splicing coupled with nonsense-mediated decay

Cited by 60 publications

References 50 publications

Coordinated tissue-specific regulation of adjacent alternative 3′ splice sites inC. elegans

Coordinated tissue-specific regulation of adjacent alternative 3′ splice sites inC. elegans

The Clothes Make the mRNA: Past and Present Trends in mRNP Fashion

Regulation of mRNA Abundance by Polypyrimidine Tract-Binding Protein-Controlled Alternate 5′ Splice Site Choice

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