Mechanisms and Regulation of Alternative Pre-mRNA Splicing

By Yeon J. Lee, D. Rio. Annual Review of Biochemistry, 2015

1,142 citations recorded by the source corpus.

Precursor messenger RNA (pre-mRNA) splicing is a critical step in the posttranscriptional regulation of gene expression, providing significant expansion of the functional proteome of eukaryotic organisms with limited gene numbers. Split eukaryotic genes contain intervening sequences or introns disrupting protein-coding exons, and intron removal occurs by repeated assembly of a large and highly dynamic ribonucleoprotein complex termed the spliceosome, which is composed of five small nuclear ribonucleoprotein particles, U1, U2, U4/U6, and U5. Biochemical studies over the past 10 years have allowed the isolation as well as compositional, functional, and structural analysis of splicing complexes at distinct stages along the spliceosome cycle. The average human gene contains eight exons and seven introns, producing an average of three or more alternatively spliced mRNA isoforms. Recent high-throughput sequencing studies indicate that 100% of human genes produce at least two alternative mRNA isoforms. Mechanisms of alternative splicing include RNA–protein interactions of splicing factors with regulatory sites termed silencers or enhancers, RNA–RNA base-pairing interactions, or chromatin-based effects that can change or determine splicing patterns. Disease-causing mutations can often occur in splice sites near intron borders or in exonic or intronic RNA regulatory silencer or enhancer elements, as well as in genes that encode splicing factors. Together, these studies provide mechanistic insights into how spliceosome assembly, dynamics, and catalysis occur; how alternative splicing is regulated and evolves; and how splicing can be disrupted by cis- and trans-acting mutations leading to disease states. These findings make the spliceosome an attractive new target for small-molecule, antisense, and genome-editing therapeutic interventions.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/45158d7a8727fc022eae96843b72ece43e3f7236

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Citations in the corpus

15 years of PhosphoSitePlus®: integrating post-translationally modified sites, disease variants and isoforms (2018, background): “Alternative isoform usage plays important roles in many biological processes (26,27).”
SUPPA2: fast, accurate, and uncertainty-aware differential splicing analysis across multiple conditions (2018, neutral): “Alternative splicing is related to a change in the relative abundance of transcript isoforms produced from the same gene [1].”
The pre-mRNA splicing and transcription factor Tat-SF1 is a functional partner of the spliceosome SF3b1 subunit via a U2AF homology motif interface (2018, background): “We conclude that whereas SF3b1 serves Tat-SF1independent functions as a major spliceosome subunit (42), a feedback mechanism modulates Tat-SF1 levels in response to SF3b1.”
Small molecule modulators of pre-mRNA splicing in cancer therapy (2015, background): “single pre-mRNA molecule by the combinatorial use of splice sites [3, 4].”
Dynamic transcriptomic m6A decoration: writers, erasers, readers and functions in RNA metabolism (2018, background): “In addition to RNA-protein interactions, RNA-RNA base pairing, chromatin modifications, small RNAs, and RNA polymerase II complex have also been reported to regulate alternative splicing patterns.(128,130) Recently, several lines of evidence indicated that m(6)A also serves as an important pre-mRNA ”
The nuts and bolts of the endogenous spliceosome (2017, background): “Another element that affect AS is the promoter, as different promoters that vary in the recruitment of transcription factors have different effect on alternative splicing.(58,59,86,87) A ‘kinetic model’ in which cooperation between transcription and splicing affects AS was proposed, in which alterna”