NMD (nonsense-mediated mRNA decay) belongs to the best-studied mRNA surveillance systems of the cell, limiting the synthesis of truncated and potentially harmful proteins on the one hand and playing an initially unexpected role in the regulation of global gene expression on the other hand. In the present review, we briefly discuss the factors involved in NMD, the different models proposed for the recognition of PTCs (premature termination codons), the diverse physiological roles of NMD, the involvement of this surveillance pathway in disease and the current strategies for medical treatment of PTC-related diseases.
We have studied the splicing regulation of NF1 exons 36 and 37. We show that they not only require an intact exon Splicing Enhancer (ESE) within exon 37, but also need the genomic region stretching from exons 31 to 38. Any nucleotide change in two exon 37 third codon positions disrupts the ESE. The extent of exons 36 and 37 skipping due to a mutated ESE depends on the genomic context. This is a unique example of what may be a more general phenomena involved in the tuning of pre-mRNA processing and gene expression modulation in the chromosomal setting.
Nonsense-mediated RNA decay (NMD) is an RNA-based quality control mechanism that eliminates
transcripts bearing premature translation termination codons (PTC). Approximately, one-third of all
inherited disorders and some forms of cancer are caused by nonsense or frame shift mutations that
introduce PTCs, and NMD can modulate the clinical phenotype of these diseases. 5-azacytidine is an
analogue of the naturally occurring pyrimidine nucleoside cytidine, which is approved for the
treatment of myelodysplastic syndrome and myeloid leukemia. Here, we reveal that 5-azacytidine
inhibits NMD in a dose-dependent fashion specifically upregulating the expression of both
PTC-containing mutant and cellular NMD targets. Moreover, this activity of 5-azacytidine depends on
the induction of MYC expression, thus providing a link between the effect of this drug and one of
the key cellular pathways that are known to affect NMD activity. Furthermore, the effective
concentration of 5-azacytidine in cells corresponds to drug levels used in patients, qualifying
5-azacytidine as a candidate drug that could potentially be repurposed for the treatment of
Mendelian and acquired genetic diseases that are caused by PTC mutations.
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