INSA - Dissertações de mestrado
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- The mechanism of nonsense-mediated mRNA decay and its playersPublication . Subtil, Catarina; Loison, Luísa; Santos, Rafaela LacerdaNonsense-mediated mRNA decay (NMD) is a post-transcriptional surveillance mechanism harbouring two functions: identification and degradation of transcripts containing premature translation-termination codons (PTC), preventing deleterious effects in the cell; and downregulation of mRNAs in response to cellular needs, maintaining the quality of gene expression. One-third of gene mutations in human genetic diseases, including cancer, are due to nonsense mutations or frameshift that result in transcripts harbouring nonsense codons and can be eliminated by NMD. The several factors involved in this mechanism may act in diverse ways depending on the set of transcripts to be regulated, contributing to the branching of this pathway. Cytoplasmic DIS3 exosome independent 3′-5′ exoribonuclease 2 (DIS3L2) has been reported as one of the factors to induce NMD targets decay. Therefore, this study aims to enlighten how DIS3L2 functions in NMD: i) analyse the correlation between the distinct branches of NMD and cervical and uterus cancer; ii) investigate which branch guides DIS3L2-mediated degradation; and iii) test which region of the NMD/DIS3L2-targets mediate DIS3L2 degradation through a system of hybrid-genes. For our first aim, we detected no correlation between any of the branches of NMD and uterus and cervical cancer. Each factor acts independently. In our second objective, we analysed the mRNA expression of five transcripts, but none displayed a significant alteration in their expression to infer a correlation between DIS3L2 and a particular NMD branch. Relatively to the last aim, we successfully cloned three out of the four constructs but due to time constrictions we could not continue. Nonetheless, further testing is needed to better understand this mechanism and how transcript degradation is mediated, including the diverse factors needed for its activation, which might be the key to future advanced therapeutic strategies.