Mechanism and Role of Nonsense-mediated mRNA Decay (NMD)

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  • ナンセンス変異依存mRNA分解機構(NMD)の機構と役割について

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Abstract

Some cases of recessive genetic disease are caused by nonsense-mutation (premature stop codon) and mRNA that contains this type of mutation is rapidly degraded by a mRNA decay pathway termed nonsense-mediated mRNA decay (NMD, or RNA surveillance). The biological role of NMD is thought to be the knocking down of abnormal mRNA that encodes potentially deleterious truncated protein. In addition to naturally occurring nonsense-containing mRNAs originating from genetic mutations, abnormally spliced mRNAs and some edited mRNAs are also degraded by NMD. NMD pathway is dependent on pre-mRNA splicing, PI-3 kinase dependent phosphorylation and translation. Splicing deposits a complex at 50-55nt upstream of exon-exon junction, and this exon junction complex (EJC) recruits NMD factors (Upf1, Upf2 and Upf3s) onto mRNA molecule. NMD seems to occur when translation terminates at stop codon derived from nonsense mutation. The terminated ribosome is thought to interact with junction-bound NMD factors via translation termination factors (eRF1 and eRF3). For eliciting abnormal mRNA degradation, the phosphorylation of NMD factors by PI-3 type kinase, SMG-1/ATX is also required. Although previously thought of as a pathway that rids the cell of deleterious mRNAs arising from mutations and processing errors, recent research suggests a more general and evolutionarily important role for NMD in the control of overall gene expression.

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