alternative polyadenylation and nonsense-mediated decay coordinately regulate the human hfe mrna levels替代聚腺苷酸化和nonsense-mediated衰变协调调节人类hfe mrna水平.pdfVIP

Alternative Polyadenylation and Nonsense-Mediated Decay Coordinately Regulate the Human HFE mRNA Levels 1 1 1 1 ´ 1 1 Rute Martins , Daniela Proenc¸a , Bruno Silva , Cristina Barbosa , Ana Luısa Silva , Paula Faustino , ´ ˜ 1,2* Luısa Romao ´ ´ 1 Departamento de Genetica, Instituto Nacional de Saude Dr. Ricardo Jorge, Lisboa, Portugal, 2 BioFIG - Center for Biodiversity, Functional and Integrative Genomics, ˆ Faculdade de Ciencias, Universidade de Lisboa, Lisboa, Portugal Abstract Nonsense-mediated decay (NMD) is an mRNA surveillance pathway that selectively recognizes and degrades defective mRNAs carrying premature translation-termination codons. However, several studies have shown that NMD also targets physiological transcripts that encode full-length proteins, modulating their expression. Indeed, some features of physiological mRNAs can render them NMD-sensitive. Human HFE is a MHC class I protein mainly expressed in the liver that, when mutated, can cause hereditary hemochromatosis, a common genetic disorder of iron metabolism. The HFE gene structure comprises seven exons; although the sixth exon is 1056 base pairs (bp) long, only the first 41 bp encode for amino acids. Thus, the remaining downstream 1015 bp sequence corresponds to the HFE 39 untranslated region (UTR), along with exon seven. Therefore, this 39 UTR encompasses an exon/exon junction, a feature that can make the corresponding physiological transcript NMD-sensitive. Here, we demonstrate that in UPF1-depleted or in cycloheximide-tre