The function of DIS3L2 in the mechanism of nonsense-mediated mRNA decay

Garcia-Moreno, Juan; da Costa, Paulo J.; Menezes, Juliane; Saramago, Margarida; Viegas, Sandra C.; Arraiano, Cecília C.; Romão, Luísa

Publication

The function of DIS3L2 in the mechanism of nonsense-mediated mRNA decay

2019-06-11Conference object

dc.contributor.author	Garcia-Moreno, Juan
dc.contributor.author	da Costa, Paulo J.
dc.contributor.author	Menezes, Juliane
dc.contributor.author	Saramago, Margarida
dc.contributor.author	Viegas, Sandra C.
dc.contributor.author	Arraiano, Cecília C.
dc.contributor.author	Romão, Luísa
dc.date.accessioned	2020-05-21T18:38:47Z
dc.date.embargo	2025-12-31
dc.date.issued	2019-06-11
dc.description.abstract	In the flow of information from DNA to mRNA to proteins, mRNAs undergo a number of processing steps, since they are synthesized in the nucleus, until they are translated in the cytoplasm. Eukaryotic cells tightly control the fidelity of this process, via quality control pathways, among them, the nonsense-mediated mRNA decay (NMD). NMD recognizes and degrades mRNAs harboring premature translation-termination codons (PTCs), protecting the cell from potentially harmful truncated proteins. However, NMD can also regulate normal and fully functional mRNA levels, arising as a surveillance and a gene expression regulation pathway. A new branch of the NMD pathway is starting to be revealed, which is characterized by the involvement of the DIS3L2 3’ to 5’ exoribonuclease. This protein has special relevance, given its exosome-independent action and its uridylation-mediated decay. In addition, mutations on this ribonuclease induce deregulation of cell-cycle genes leading to a faster cell growth and decreased chromosome stability, while DIS3L2 downregulation enhances cancer stem cell properties. Several lines of evidence point to an oncogenic role of DIS3L2 and its mediated decay over a number of NMD targets, however further research is needed to unveil the mechanism by which this nuclease is involved in NMD and how it mediates cancer related processes. In this work, we show the DIS3L2 involvement in the NMD target regulation, by its dependent action on the NMD central player, UPF1. We also aim to analyze how DIS3L2 and uridylation regulate the human transcriptome, in order to shed light on how this ribonuclease is related to NMD and how its deregulation contributes to tumorigenesis. For this purpose, high-throughput mRNA sequencing has been performed in the SW480 colorectal cancer cell line depleted of DIS3L2 or DIS3L2 plus terminal uridylyl transferases (TUTases), TUT4 and TUT7.	pt_PT
dc.description.sponsorship	This work was partially supported by Fundação para a Ciência e a Tecnologia (FCT), Portugal (PTFC/BIM-MEC/3749/2014 to LR and UID/MULTI/04046/2013 centre grant to BioISI). PJdC and JFG-M are recipients of a fellowship from BioSys PhD programme (SFRH/BD/52495/2014 to PJdC, SFRH/BD/52492/2014 to HAS, and PD/BD/142898/2018 to JFG-M) 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 (Microbiologia Molecular, Estrutural e Celular) funded by the European Regional Development Fund (FEDER) through COMPETE2020 - Programa Operacional Competitividade e Internacionalização (POCI) and by national funds through FCT: project PTDC/BIAMIC/1399/2014 to CMA and project PTFC/BIM-MEC/3749/2014 to SCV. SCV was financed by program IF of FCT [ref. IF/00217/2015]. MS was financed by an FCT grant [SFRH/BPD/109464/2015]. We thank Dr. V. Narry Kim from Seoul National University (Seoul, Korea), who kindly provided us with the pCK-FLAG-TUT4 and pCK-FLAG-TUT7 vectors.	pt_PT
dc.description.version	info:eu-repo/semantics/publishedVersion	pt_PT
dc.identifier.uri	http://hdl.handle.net/10400.18/6743
dc.language.iso	eng	pt_PT
dc.peerreviewed	yes	pt_PT
dc.rights.uri	http://creativecommons.org/licenses/by-nc/4.0/	pt_PT
dc.subject	mRNA Decay	pt_PT
dc.subject	DIS3L2	pt_PT
dc.subject	Doenças Genéticas	pt_PT
dc.subject	Genómica Funcional e Estrutural	pt_PT
dc.title	The function of DIS3L2 in the mechanism of nonsense-mediated mRNA decay	pt_PT
dc.type	conference object
dspace.entity.type	Publication
oaire.citation.conferencePlace	Cracóvia, Polónia	pt_PT
oaire.citation.title	24th Annual Meeting of the RNA Society, 11 June-16 June 2019	pt_PT
rcaap.rights	embargoedAccess	pt_PT
rcaap.type	conferenceObject	pt_PT