A role for DIS3L2 over natural nonsense-mediated mRNA decay targets in human cells

Costa, Paulo J. da; Menezes, Juliane; Saramago, Margarida; García-Moreno, Juan F.; Santos, Hugo A.; Gama-Carvalho, Margarida; Arraiano, Cecília M.; Romão, Luísa

http://hdl.handle.net/10400.18/6466

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Authors

Costa, Paulo J. da

Menezes, Juliane

Saramago, Margarida

García-Moreno, Juan F.

Santos, Hugo A.

Gama-Carvalho, Margarida

Arraiano, Cecília M.

Romão, Luísa

Abstract(s)

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.

Description

Supplementary data to this article can be found online at https://doi.org/10.1016/j.bbrc.2019.08.105.

Keywords

Nonsense-mediated mRNA Decay NMD DIS3L2 Terminal Uridylyl Transferases Zcchc6/11 TUT7/4 mRNA Turnover Doenças Genéticas Genómica Funcional e Estrutural