Costa, Paulo J. daMenezes, JulianeSaramago, MargaridaGarcía-Moreno, Juan F.Santos, Hugo A.Gama-Carvalho, MargaridaArraiano, Cecília M.Romão, Luísa2020-04-202020-10-222019-10-22Biochem Biophys Res Commun. 2019 Oct 22;518(4):664-671. doi: 10.1016/j.bbrc.2019.08.105. Epub 2019 Aug 26.0006-291Xhttp://hdl.handle.net/10400.18/6466Supplementary data to this article can be found online at https://doi.org/10.1016/j.bbrc.2019.08.105.The nonsense-mediated decay (NMD) pathway selectively degrades mRNAs carrying a premature translation-termination codon but also regulates the abundance of a large number of physiological mRNAs that encode full-length proteins. In human cells, NMD-targeted mRNAs are degraded by endonucleolytic cleavage and exonucleolytic degradation from both 5-' and 3'-ends. This is done by a process not yet completely understood that recruits decapping and 5'-to-3' exonuclease activities, as well as deadenylating and 3'-to-5' exonuclease exosome activities. In yeast, DIS3/Rrp44 protein is the catalytic subunit of the exosome, but in humans, there are three known paralogues of this enzyme: DIS3, DIS3L1, and DIS3L2. However, little is known about their role in NMD. Here, we show that some NMD-targets are DIS3L2 substrates in human cells. In addition, we observed that DIS3L2 acts over full-length transcripts, through a process that also involves UPF1. Moreover, DIS3L2-mediated decay is dependent on the activity of the terminal uridylyl transferases Zcchc6/11 (TUT7/4). Together, our findings establish a role for DIS3L2 and uridylation in NMD.Highlights: DIS3L2 functions in the decay of natural NMD-targets in a transcript-specific manner; DIS3L2 acts over full-length NMD-targets, through a process that also involves UPF1; DIS3L2 function in NMD is dependent on the terminal uridylyl transferases Zcchc6/11.engNonsense-mediated mRNA DecayNMDDIS3L2Terminal Uridylyl Transferases Zcchc6/11TUT7/4mRNA TurnoverDoenças GenéticasGenómica Funcional e Estruturaljournal article10.1016/j.bbrc.2019.08.105