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Please use this identifier to cite or link to this item: http://hdl.handle.net/10451/1606

Title: Study of the nonsense-mediated decay (NMD) mechanism in the human \03B1-globin mRNA
Authors: Pereira, Francisco José Cabral, 1978-
Advisor: Loison, Luísa Romão, 1963-
Amaral, Margarida, 1958-
Keywords: Genética molecular
Teses de doutoramento
Issue Date: 2009
Abstract: Eukaryotic cells have developed mechanisms to regulate many steps of gene expression, preventing defective protein production and ensuring cell survival. Nonsense-mediated mRNA decay (NMD) is a posttranscriptional surveillance pathway able to recognize and eliminate transcripts encoding truncated proteins. In mammalian cells, mRNAs containing premature translation termination codons (PTCs) placed more than 50-55 nucleotides upstream from the last exon-exon junction are generally committed to NMD. However, transcripts carrying a nonsense codon in this condition, located near the translation initiation codon, have been reported to escape decay. The present work contains the description of a clinical case where a PTC, caused by a single nucleotide deletion in the human -globin mRNA, induces accelerated mRNA degradation. On the other hand, data reveals that stop codons located in the first exon of the -globin transcript fail to induce NMD. This resistance to decay is further downstream extended when compared with the equivalent effect observed in the human -globin mRNA, and this divergence is shown to be mainly determined by the sequence upstream to the PTC and the secondary structure of the open reading frame (ORF). Contrary to -globin, the  globin mRNA allows translation reinitiation at a downstream AUG, after translation of a short ORF. However, NMD inhibition persists even when translation reinitiation is prevented. Results suggest that a less-structured short ORF is more rapidly translated and NMD-antagonistic factors, such as PABPC1, may remain associated with the ribosome when it reaches the stop codon. This work constitutes a basic research development with confirmed and potential scientific diffusion, and contributes with prospective benefits in public health, since its results may provide targets for new therapeutic strategies for genetic disorders caused by PTC-generating mutations.
Description: Tese de doutoramento, Biologia (Genética Molecular), 2009, Universidade de Lisboa, Faculdade de Ciências
URI: http://catalogo.ul.pt/F/?func=item-global&doc_library=ULB01&type=03&doc_number=000556096
http://hdl.handle.net/10451/1606
Appears in Collections:FC - Teses de Doutoramento

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