Supplementary 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.This work was partially supported by Fundaçao para a Ci ~ encia e ^
a Tecnologia (FCT) (PTFC/BIM-MEC/3749/2014 to LR and UID/
MULTI/04046/2013 to BioISI). PJdC, HAS and JFG-M are recipients of
a fellowship from BioSys PhD programme (SFRH/BD/52495/2014,
SFRH/BD/52492/2014, and PD/BD/142898/2018, respectively) and
JM is a posdoc fellow (SFRH/BPD/98360/2013) from FCT. Work at
ITQB-NOVA was financially supported by: Project LISBOA-01-0145-FEDER-007660 funded by the European Regional Development
Fund (FEDER) through COMPETE2020 - Programa Operacional
Competitividade e Internacionalizaçao (POCI) and by FCT funds: ~
PTDC/BIA-MIC/1399/2014 to CMA and PTDC/BIM-MEC/3749/2014
to SCV. SCV was financed by program IF of FCT (IF/00217/2015). MS
was financed by an FCT contract according to DL57/2016 [SFRH/
BPD/109464/2015]. We thank Dr. V. Narry Kim from Seoul National
University, who kindly provided us with the pCK-FLAG-TUT4 and
pCK-FLAG-TUT7 vectors.info:eu-repo/semantics/publishedVersio
