Browsing by Author "García-Moreno, Juan"
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- Functional networks of DI3L2 in cancerPublication . García-Moreno, Juan; Matos, Paulo; Romão, LuísaThe DIS3-like 3′-5′ exoribonuclease 2 (DIS3L2) triggers decay in an exosome-independent manner and preferentially degrades RNA species possessing a non-templated oligo-uridine 3’-end tail. It is capable of inducing decay over a variety of RNAs, including mRNAs, rRNAs, miRNAs and other non-coding RNAs. It has been shown that DIS3L2 is involved in cancer-related cellular processes. Nevertheless, its function in tumorigenesis remains largely unexplored. Recently, we and others showed that DIS3L2-mediated decay together with uridylation also participate in nonsense-mediated mRNA decay (NMD), thus revealing a new NMD branch. NMD is a surveillance pathway that recognizes and degrades mRNAs harboring premature translation-termination codons, protecting the cell from potentially harmful truncated proteins. However, NMD also regulates the level of normal and fully functional mRNAs, arising as a mechanism of gene expression regulation. Here, we 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 4 and 7. Gene ontology analysis over the set of genes up-regulated under those two conditions, show enrichment in molecular functions and biological processes related with cancer, and cell events directly implicated in RNA processing and RNA degradation. Preliminary results on the features of the deregulated transcripts also show significant differences between conditions, an important aspect that is guiding us to determine grades of sensitivities in the decay of DIS3L2-subtrates. Currently, we are unveiling the role of DIS3L2 in oncogenesis and analyzing its substrate specificity.
- Functional networks of DIS3L2 in cancer and NMDPublication . García-Moreno, Juan; da Costa, Paulo J; Menezes, Juliane; Pereira, Marcelo; Gama-Carvalho, Margarida; Matos, Paulo; Romão, LuísaIn 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 project, we 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. Preliminary results show gene ontology enrichment in molecular functions and biological processes related with cancer.
- Perspective in Alternative Splicing Coupled to Nonsense-Mediated mRNA DecayPublication . García-Moreno, Juan; Romão, LuísaAlternative splicing (AS) of precursor mRNA (pre-mRNA) is a cellular post-transcriptional process that generates protein isoform diversity. Nonsense-mediated RNA decay (NMD) is an mRNA surveillance pathway that recognizes and selectively degrades transcripts containing premature translation-termination codons (PTCs), thereby preventing the production of truncated proteins. Nevertheless, NMD also fine-tunes the gene expression of physiological mRNAs encoding full-length proteins. Interestingly, around one third of all AS events results in PTC-containing transcripts that undergo NMD. Numerous studies have reported a coordinated action between AS and NMD, in order to regulate the expression of several genes, especially those coding for RNA-binding proteins (RBPs). This coupling of AS to NMD (AS-NMD) is considered a gene expression tool that controls the ratio of productive to unproductive mRNA isoforms, ultimately degrading PTC-containing non-functional mRNAs. In this review, we focus on the mechanisms underlying AS-NMD, and how this regulatory process is able to control the homeostatic expression of numerous RBPs, including splicing factors, through auto- and cross-regulatory feedback loops. Furthermore, we discuss the importance of AS-NMD in the regulation of biological processes, such as cell differentiation. Finally, we analyze interesting recent data on the relevance of AS-NMD to human health, covering its potential roles in cancer and other disorders.