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.