Transcriptome-wide identification of NMD-targeted human mRNAs reveals extensive redundancy between SMG6- and...

Area of Science:

• Molecular Biology
• Genetics
• RNA Biology

Background:

• Nonsense-mediated mRNA decay (NMD) is a surveillance pathway that degrades aberrant mRNAs with premature translation termination codons (PTCs).
• However, NMD also targets numerous seemingly normal mRNAs encoding full-length proteins, but a comprehensive set of these endogenous targets remains elusive.

Purpose of the Study:

• To identify a reliable set of endogenous NMD targets in human cells.
• To characterize sequence features that predict NMD targeting.

Main Methods:

• A meta-analysis approach combining transcriptome profiling from knockdowns and rescues of NMD factors UPF1, SMG6, and SMG7.
• Comparative analysis of NMD-targeted versus NMD-insensitive transcripts.

Main Results:

• The combinatorial meta-analysis approach reliably identified NMD targets, outperforming previous methods.
• SMG6 and SMG7 exhibit functional redundancy, targeting largely overlapping sets of transcripts.
• Beyond mRNAs, NMD targets long noncoding RNAs, miRNA, and snoRNA host genes.
• Key features predicting NMD targeting include 3' UTR introns, upstream open reading frames (uORFs), and long 3' UTRs.
• NMD-targeted transcripts show increased 3' UTR GC content and reduced phylogenetic conservation.

Conclusions:

• This study provides a robust identification of endogenous NMD targets, expanding the known scope of NMD regulation.
• The findings highlight sequence features that can predict NMD targeting, aiding in understanding mRNA regulation.
• The redundancy between SMG6 and SMG7 underscores the complex interplay of decay pathways.