hnRNP A1 and the SR proteins ASF/SF2 and SC35 have antagonistic functions in splicing of beta-tropomyosin exon 6B

J Biol Chem. 2004 Sep 10;279(37):38249-59. doi: 10.1074/jbc.M405377200. Epub 2004 Jun 18.

Abstract

Mutually exclusive splicing of exons 6A and 6B from the chicken beta-tropomyosin gene involves numerous regulatory sequences. Previously, we identified a G-rich intronic sequence (S3) downstream of exon 6B. This element consists of six G-rich motifs, mutations of which abolish splicing of exon 6B. In this paper, we investigated the cellular factors that bind to this G-rich element. By using RNA affinity chromatography, we identified heterogeneous nuclear ribonucleoprotein (hnRNP) A1, the SR proteins ASF/SF2 and SC35, and hnRNP F/H as specific components that are assembled onto the G-rich element. By using hnRNP A1-depleted HeLa nuclear extract and add-back experiments, we show that hnRNP A1 has a negative effect on splicing of exon 6B. In agreement with in vitro data, artificial recruitment of hnRNP A1, as a fusion with the MS2 coat protein, also represses splicing of exon 6B ex vivo. In contrast, ASF/SF2 and SC35 activate splicing of exon 6B. As observed with other systems, hnRNP A1 counteracts the stimulating effect of the SR proteins. Moreover, cross-linking experiments show that both ASF/SF2 and SC35 are able to displace binding of hnRNP A1 to the G-rich element, suggesting that the binding sites for these proteins are overlapping. These data indicate that the G-rich sequence is a composite element that acts as an enhancer or as a silencer, depending on which proteins bind to them.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing*
  • Amino Acid Motifs
  • Animals
  • Base Sequence
  • Binding Sites
  • Blotting, Western
  • Cell Nucleus / metabolism
  • Chickens
  • Chromatography, Affinity
  • Cross-Linking Reagents / pharmacology
  • Exons
  • Gene Silencing
  • Genes, Reporter
  • HeLa Cells
  • Heterogeneous Nuclear Ribonucleoprotein A1
  • Heterogeneous-Nuclear Ribonucleoprotein Group A-B / physiology*
  • Heterogeneous-Nuclear Ribonucleoproteins / chemistry
  • Humans
  • Introns
  • Mass Spectrometry
  • Models, Genetic
  • Molecular Sequence Data
  • Mutation
  • Nuclear Proteins / physiology*
  • Plasmids / metabolism
  • Protein Binding
  • Protein Structure, Tertiary
  • RNA / chemistry
  • RNA Precursors
  • RNA Splicing
  • RNA, Messenger / metabolism
  • RNA-Binding Proteins
  • Recombinant Proteins / chemistry
  • Ribonucleoproteins / physiology*
  • Sequence Homology, Nucleic Acid
  • Serine-Arginine Splicing Factors
  • Transcription, Genetic
  • Transfection
  • Tropomyosin / genetics*
  • Tropomyosin / metabolism*
  • Ultraviolet Rays

Substances

  • Cross-Linking Reagents
  • Heterogeneous Nuclear Ribonucleoprotein A1
  • Heterogeneous-Nuclear Ribonucleoprotein Group A-B
  • Heterogeneous-Nuclear Ribonucleoproteins
  • Nuclear Proteins
  • RNA Precursors
  • RNA, Messenger
  • RNA-Binding Proteins
  • Recombinant Proteins
  • Ribonucleoproteins
  • Tropomyosin
  • SRSF2 protein, human
  • Serine-Arginine Splicing Factors
  • RNA