title: How Are Short Exons Flanked by Long Introns Defined and Committed to Splicing?
abstract: The splice sites (SSs) delimiting an intron are brought together in the earliest step of spliceosome assembly yet it remains obscure how SS pairing occurs, especially when introns are thousands of nucleotides long. Splicing occurs in vivo in mammals within minutes regardless of intron length, implying that SS pairing can instantly follow transcription. Also, factors required for SS pairing, such as the U1 small nuclear ribonucleoprotein (snRNP) and U2AF65, associate with RNA polymerase II (RNAPII), while nucleosomes preferentially bind exonic sequences and associate with U2 snRNP. Based on recent publications, we assume that the 5' SS-bound U1 snRNP can remain tethered to RNAPII until complete synthesis of the downstream intron and exon. An additional U1 snRNP then binds the downstream 5' SS, whereas the RNAPII-associated U2AF65 binds the upstream 3' SS to facilitate SS pairing along with exon definition. Next, the nucleosome-associated U2 snRNP binds the branch site to advance splicing complex assembly. This may explain how RNAPII and chromatin are involved in spliceosome assembly and how introns lengthened during evolution with a relatively minimal compromise in splicing.
authors: Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv 69978, Israel.
authors: Dror
authors: D
authors: Hollander
authors: Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv 69978, Israel.
authors: Shiran
authors: S
authors: Naftelberg
authors: Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv 69978, Israel.
authors: Galit
authors: G
authors: Lev-Maor
authors: IFIBYNE-UBA-CONICET and Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Pabellón II, C1428EHA Buenos Aires, Argentina.
authors: Alberto R
authors: AR
authors: Kornblihtt
authors: Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv 69978, Israel. Electronic address: gilast@post.tau.ac.il.
authors: Gil
authors: G
authors: Ast
mesh_terms: D002843:Chromatin / Q000235:genetics; D005091:Exons / Q000235:genetics; D006801:Humans; D007438:Introns / Q000235:genetics; D012319:RNA Polymerase II / Q000235:genetics*; D012326:RNA Splicing / Q000235:genetics*; D017412:Ribonucleoprotein, U1 Small Nuclear; D017411:Ribonucleoproteins, Small Nuclear / Q000235:genetics*; D017381:Spliceosomes / Q000235:genetics; D000072668:Splicing Factor U2AF / Q000235:genetics*
chemical_list: D002843:Chromatin; D017412:Ribonucleoprotein, U1 Small Nuclear; D017411:Ribonucleoproteins, Small Nuclear; D000072668:Splicing Factor U2AF; C000607494:U2AF2 protein, human; D012319:RNA Polymerase II