DIS3L2 and Nonsense-mediated Decay: United to Degrade

Nonsense-mediated decay (NMD) is a vital RNA surveillance mechanism in eukaryotic cells that ensures mRNA quality and regulates gene expression. NMD targets mRNAs with premature translation-termination codons to prevent the production of potentially harmful truncated proteins. But NMD is also involved in modulating the expression of physiological mRNAs to maintain cellular homeostasis. This NMD function is particularly relevant to calibrate the cellular transcriptome in response to environmental signals and stress. Its conservation across eukaryotes highlights its essential role. When active, NMD promotes mRNA degradation involving exoribonucleases such as XRN1 (5'-3') and the exosome (3'-5'). DIS3L2, an exosome-independent exonuclease that primarily targets substrates marked by the non-templated addition of uridine residues to the 3' end of RNA molecules by terminal uridylyl transferases, can also degrade some NMD substrates, especially those that underwent 3' end uridylation. This review explores DIS3L2's interaction with the NMD pathway (DIS3L2/NMD pathway) and the human disorders associated with a dysfunctional DIS3L2/NMD pathway. A better understanding of the interplay between NMD and DIS3L2 will certainly allow the development of novel treatments for disorders associated with an affected DIS3L2/NMD pathway.