Regulatory Role of Upstream Open Reading Frames in RNA Degradation by Nonsense-Mediated Decay

Many eukaryotic mRNAs contain upstream ORFs (uORFs) located in the 5’-UTR along with the main protein-coding open reading frame (ORF). uORFs are known as post-transcriptional cis-regulatory elements since they modulate translation of main ORF or may even cause mRNA degradation by Nonsense-Mediated Decay (NMD) pathway, both leading to altered gene expression. With usage of RNA-sequencing data obtained from HEK293 human cell line in response to the depletion of major factors involved in NMD we aim to assess the scope of mRNA degradation induced by uORFs. This work shows that in general genes with uORFs respond to NMD repression more actively than other genes do. Moreover, in some genes the isoform switch between mRNAs with uORFs and those without is observed when NMD is inactivated. This suggests that autoregulatory loops that alter the inclusion of the uORF-containing exon may exist in some genes, ones that are similar to the autoregulatory feedback loop of alternative splicing coupled with NMD.