Direct Competition between hnRNP C and U2AF65 Protects the Transcriptome from the Exonization of Alu Elements.
Direct Competition between hnRNP C and U2AF65 Protects the
Transcriptome from the Exonization of Alu Elements.
Kathi Zarnack, Julian König, Mojca Tajnik, Iñigo Martincorena, Sebastian Eustermann, Isabelle Stévant, Alejandro Reyes, Simon Anders, Nicholas M Luscombe, and Jernej Ule
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.
Cell, 2013 vol. 152 (3) pp. 453-466
http://www.sciencedirect.com/science/article/pii/S0092867412015450
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