title: Direct competition between hnRNP C and U2AF65 protects the transcriptome from the exonization of Alu elements.
abstract: 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.
authors: European Molecular Biology Laboratory (EMBL) European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
authors: Kathi
authors: K
authors: Zarnack
authors: Julian
authors: J
authors: König
authors: Mojca
authors: M
authors: Tajnik
authors: Iñigo
authors: I
authors: Martincorena
authors: Sebastian
authors: S
authors: Eustermann
authors: Isabelle
authors: I
authors: Stévant
authors: Alejandro
authors: A
authors: Reyes
authors: Simon
authors: S
authors: Anders
authors: Nicholas M
authors: NM
authors: Luscombe
authors: Jernej
authors: J
authors: Ule
mesh_terms: D020087:Alu Elements; D019143:Evolution, Molecular; D005091:Exons; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D034482:Heterogeneous-Nuclear Ribonucleoprotein Group C / Q000235:genetics / Q000378:metabolism*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D047468:Immunoprecipitation; D009687:Nuclear Proteins / Q000378:metabolism*; D022821:RNA Splice Sites; D012261:Ribonucleoproteins / Q000378:metabolism*; D017423:Sequence Analysis, RNA; D000072668:Splicing Factor U2AF; D059467:Transcriptome
chemical_list: D034482:Heterogeneous-Nuclear Ribonucleoprotein Group C; D009687:Nuclear Proteins; D022821:RNA Splice Sites; D012261:Ribonucleoproteins; D000072668:Splicing Factor U2AF; C000607494:U2AF2 protein, human
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