Direct competition between hnRNP C and U2AF65 protects the transcriptome from the exonization of Alu elements

Cell. 2013 Jan 31;152(3):453-66. doi: 10.1016/j.cell.2012.12.023.


There are ~650,000 Alu elements in transcribed regions of the human genome. These elements contain cryptic splice sites, so they are in constant danger of aberrant incorporation into mature transcripts. Despite posing a major threat to transcriptome integrity, little is known about the molecular mechanisms preventing their inclusion. Here, we present a mechanism for protecting the human transcriptome from the aberrant exonization of transposable elements. Quantitative iCLIP data show that the RNA-binding protein hnRNP C competes with the splicing factor U2AF65 at many genuine and cryptic splice sites. Loss of hnRNP C leads to formation of previously suppressed Alu exons, which severely disrupt transcript function. Minigene experiments explain disease-associated mutations in Alu elements that hamper hnRNP C binding. Thus, by preventing U2AF65 binding to Alu elements, hnRNP C plays a critical role as a genome-wide sentinel protecting the transcriptome. The findings have important implications for human evolution and disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alu Elements*
  • Evolution, Molecular
  • Exons
  • Gene Expression Profiling
  • Gene Knockdown Techniques
  • HeLa Cells
  • Heterogeneous-Nuclear Ribonucleoprotein Group C / genetics
  • Heterogeneous-Nuclear Ribonucleoprotein Group C / metabolism*
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Immunoprecipitation
  • Nuclear Proteins / metabolism*
  • RNA Splice Sites
  • Ribonucleoproteins / metabolism*
  • Sequence Analysis, RNA
  • Splicing Factor U2AF
  • Transcriptome*


  • Heterogeneous-Nuclear Ribonucleoprotein Group C
  • Nuclear Proteins
  • RNA Splice Sites
  • Ribonucleoproteins
  • Splicing Factor U2AF
  • U2AF2 protein, human