title: Pre-mRNA splicing is facilitated by an optimal RNA polymerase II elongation rate.
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.
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, Colorado 80045, USA;
authors.forename: Nova
authors.initials: N
authors.lastname: Fong
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, Colorado 80045, USA;
authors.forename: Hyunmin
authors.initials: H
authors.lastname: Kim
authors.affiliation: Department of Cellular and Molecular Medicine, Institute of Genomic Medicine, University of California at San Diego, San Diego, California 92093, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Cellular and Molecular Medicine, Institute of Genomic Medicine, University of California at San Diego, San Diego, California 92093, USA.
authors.forename: Xiong
authors.initials: X
authors.lastname: Ji
authors.affiliation: Department of Cellular and Molecular Medicine, Institute of Genomic Medicine, University of California at San Diego, San Diego, California 92093, USA.
authors.forename: Jinsong
authors.initials: J
authors.lastname: Qiu
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, Colorado 80045, USA;
authors.forename: Tassa
authors.initials: T
authors.lastname: Saldi
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, Colorado 80045, USA;
authors.forename: Katrina
authors.initials: K
authors.lastname: Diener
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, Colorado 80045, USA;
authors.forename: Ken
authors.initials: K
authors.lastname: Jones
authors.affiliation: Department of Cellular and Molecular Medicine, Institute of Genomic Medicine, University of California at San Diego, San Diego, California 92093, USA.
authors.forename: Xiang-Dong
authors.initials: XD
authors.lastname: Fu
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, Colorado 80045, USA; david.bentley@ucdenver.edu.
authors.forename: David L
authors.initials: DL
authors.lastname: Bentley
mesh_terms: D005091:Exons / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D007438:Introns / Q000235:genetics; D009154:Mutation; D012319:RNA Polymerase II / Q000235:genetics / Q000378:metabolism*; D012322:RNA Precursors / Q000235:genetics / Q000378:metabolism*; D012326:RNA Splicing; D061805:Transcription Elongation, Genetic / Q000502:physiology*
chemical_list: D012322:RNA Precursors; D012319:RNA Polymerase II
keywords: alternative splicing; cotranscriptional splicing; intron retention; kinetic coupling; transcription elongation rate