The intronic splicing code: multiple factors involved in ATM pseudoexon definition

Ashish Dhir, Emanuele Buratti, Maria A van Santen, Reinhard Lührmann, Francisco E Baralle

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Abundance of pseudo splice sites in introns can potentially give rise to innumerable pseudoexons, outnumbering the real ones. Nonetheless, these are efficiently ignored by the splicing machinery, a process yet to be understood completely. Although numerous 5' splice site-like sequences functioning as splicing silencers have been found to be enriched in predicted human pseudoexons, the lack of active pseudoexons pose a fundamental challenge to how these U1snRNP-binding sites function in splicing inhibition. Here, we address this issue by focusing on a previously described pathological ATM pseudoexon whose inhibition is mediated by U1snRNP binding at intronic splicing processing element (ISPE), composed of a consensus donor splice site. Spliceosomal complex assembly demonstrates inefficient A complex formation when ISPE is intact, implying U1snRNP-mediated unproductive U2snRNP recruitment. Furthermore, interaction of SF2/ASF with its motif seems to be dependent on RNA structure and U1snRNP interaction. Our results suggest a complex combinatorial interplay of RNA structure and trans-acting factors in determining the splicing outcome and contribute to understanding the intronic splicing code for the ATM pseudoexon.

Original languageEnglish
Pages (from-to)749-60
Number of pages12
JournalEMBO Journal
Volume29
Issue number4
DOIs
Publication statusPublished - 17 Feb 2010

Keywords / Materials (for Non-textual outputs)

  • Ataxia Telangiectasia/genetics
  • Ataxia Telangiectasia Mutated Proteins
  • Base Sequence
  • Binding Sites/genetics
  • Cell Cycle Proteins/genetics
  • DNA Primers/genetics
  • DNA-Binding Proteins/genetics
  • Exons
  • Heterogeneous Nuclear Ribonucleoprotein A1
  • Heterogeneous-Nuclear Ribonucleoprotein Group A-B/metabolism
  • Humans
  • Introns
  • Models, Biological
  • Molecular Sequence Data
  • Nuclear Proteins/metabolism
  • Nucleic Acid Conformation
  • Protein-Serine-Threonine Kinases/genetics
  • RNA Precursors/chemistry
  • RNA Splice Sites
  • RNA Splicing
  • RNA-Binding Proteins
  • Recombinant Proteins/genetics
  • Ribonucleoprotein, U1 Small Nuclear/genetics
  • Ribonucleoprotein, U2 Small Nuclear/genetics
  • Sequence Deletion
  • Serine-Arginine Splicing Factors
  • Spliceosomes/genetics
  • Tumor Suppressor Proteins/genetics

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