Abstract
Nonsense-mediated messenger RNA (mRNA) decay (NMD) is a surveillance pathway used by cells to control the quality mRNAs and to fine-tune transcript abundance. NMD plays an important role in cell cycle regulation, cell viability, DNA damage response, while also serving as a barrier to virus infection. Disturbance of this control mechanism caused by genetic mutations or dys-regulation of the NMD pathway can lead to pathologies, including neurological disorders, immune diseases and cancers. The role of NMD in cancer development is complex, acting as both a promoter and a barrier to tumour progression. Cancer cells can exploit NMD for the downregulation of key tumour suppressor genes, or tumours adjust NMD activity to adapt to an aggressive immune microenvironment. The latter case might provide an avenue for therapeutic intervention as NMD inhibition has been shown to lead to the production of neoantigens that stimulate an immune system attack on tumours. For this reason, understanding the biology and co-option pathways of NMD is important for the development of novel therapeutic agents. Inhibitors, whose design can make use of the many structures available for NMD study, will play a crucial role in characterizing and providing diverse therapeutic options for this pathway in cancer and other diseases.
Highlights
IntroductionThe precise regulation of genetic information, as it is passed from gene to transcript to protein, is crucial for the survival of cells and organisms
Waga et al demonstrated that messenger RNA (mRNA) of coronaviruses (CoV) show multiple features that subject them to the Nonsense-Mediated mRNA Decay (NMD) pathway, such as multiple open-reading frames (ORFs) with internal STOP codons that make up a long 30 untranslated regions (UTRs)
A bias is observed for patients harbouring CDH1 mutations at the extreme 30 end of the gene that are able to escape from NMD
Summary
The precise regulation of genetic information, as it is passed from gene to transcript to protein, is crucial for the survival of cells and organisms. Nonsense-mediated mRNA decay (NMD) is a critical cellular surveillance mechanism that recognizes and eliminates aberrant RNAs containing premature termination codons (PTC) or abnormally long 30 untranslated regions (UTRs). Transcripts with destabilizing PTC in their coding region are products of endogenous genes with nonsense or frameshift mutations, pseudogenes [3], or from alternative splicing events leading to intron retention or inclusion of PTC-containing exons [4]. In Saccharomyces cerevisiae, PTC is defined independently of exon boundaries [5] In another variation, the presence of introns is not necessary to define PTCs in Drosophila or in Caenorhabditis elegans, which shows a mechanistic diversity in the initiation of the NMD pathway [5]. The position of the ribosome at the end of the transcript is important for translation termination, where interactions to proteins bound to the mRNA poly(A) tail and release factors are required. The resulting delayed release of the ribosome from the transcript affords the time needed to assemble NMD-related proteins and recruit other cofactors [8]
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