Dec 3, 2014

Pre-mRNA splicing is facilitated by an optimal RNA polymerase II elongation rate

Genes & Development
Nova FongDavid L Bentley

Abstract

Alternative splicing modulates expression of most human genes. The kinetic model of cotranscriptional splicing suggests that slow elongation expands and that fast elongation compresses the "window of opportunity" for recognition of upstream splice sites, thereby increasing or decreasing inclusion of alternative exons. We tested the model using RNA polymerase II mutants that change average elongation rates genome-wide. Slow and fast elongation affected constitutive and alternative splicing, frequently altering exon inclusion and intron retention in ways not predicted by the model. Cassette exons included by slow and excluded by fast elongation (type I) have weaker splice sites, shorter flanking introns, and distinct sequence motifs relative to "slow-excluded" and "fast-included" exons (type II). Many rate-sensitive exons are misspliced in tumors. Unexpectedly, slow and fast elongation often both increased or both decreased inclusion of a particular exon or retained intron. These results suggest that an optimal rate of transcriptional elongation is required for normal cotranscriptional pre-mRNA splicing.

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Mentioned in this Paper

RNA Polymerase II
Pre-mRNA Splicing
HEK293 Cells
Exons
Primary RNA Transcript
Transcription, Genetic
Neoplasms
Nuclear mRNA Cis Splicing, via Spliceosome
RNA Splicing
Mutant

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