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Spliceosomes walk the line: splicing errors and their impact on cellular function - PubMed

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Review

. 2009 Nov-Dec;6(5):526-30.

doi: 10.4161/rna.6.5.9860. Epub 2009 Nov 18.

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Review

Spliceosomes walk the line: splicing errors and their impact on cellular function

Shu-Ning Hsu et al. RNA Biol. 2009 Nov-Dec.

Abstract

The splicing of nuclear pre-mRNAs is a fundamental process required for the expression of most metazoan genes. The majority of the approximately 25,000 genes encoded by the human genome has been shown to produce more than one kind of transcripts through alternative splicing. Alternative splicing of pre-mRNAs can lead to the production of multiple protein isoforms from a single gene, significantly enriching the proteomic diversity of higher eukaryotic organisms. Because regulation of this process determines the timing and location that a particular protein isoform is produced, changes of alternative splicing patterns have the potential to modulate many cellular activities. Consequently, pre-mRNA splicing must occur with a high degree of specificity and fidelity to ensure the appropriate expression of functional mRNAs. Here we review recent progress made in understanding the extent of alternative splicing within the human genome with particular emphasis on splicing fidelity.

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Figures

Figure 1
Figure 1. Major types of alternative splicing

Boxes denote exons and horizontal lines introns. Solid lines above and dashed lines below the gene structure represent different alternative splicing events.

Figure 2
Figure 2. RNA surveillance mechanisms controlling the expression of mRNA isoforms generated through alternative splicing

The majority of pre-mRNA molecules are processed to generate protein isoforms serving diverse cellular functions (functional alternative splicing). Point mutations within the template or mis-regulation of splice site pairing can lead to erroneously spliced mRNA products (erroneous alternative splicing). A small fraction of erroneously spliced mRNAs is translated into a different protein product (bottom left) with the potential to negatively or positively influence cellular functions. The majority of erroneously spliced mRNAs will be the target of RNA surveillance mechanisms such as NMD (triggered by premature stop codons), NSD (lack of stop codon), NGD (ribosome stalling), or the rapid mammalian deadenylation-dependent decay pathway, resulting in selective degradation of erroneously spliced mRNA isoforms. The thickness of the arrows above and below the pre-mRNA reflects the frequency of these events.

Figure 3
Figure 3. The effect of TFIIS knockdown on the error rate of splice site pairing

The graph depicts the increase in erroneous splice site pairing of the constitutively spliced genes UBA52 and RPL23 as a consequence of siRNA-mediated knockdown of TFIIS, a Pol II-associated transcription factor that ensures high fidelity nucleotide insertion during RNA transcription. The y-axis shows the relative increase of splice site pairing errors in TFIIS knockdown experiments over the error rate observed in control siRNA experiments. As confirmed by quantitative real-time PCR and western blot, siRNA treatment reduced TFIIS levels by ~60% (data not shown).

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