Question

Genomic sequencing of a cell line you are researching shows a homozygous point mutation within exon 2, leading to the creation of an in-frame stop codon. Interestingly, this “premature” stop codon does not lead to NMD (nonsense-mediated decay). Explain, using a diagram, how this is possible. (5 points)

pre-MRNA: pA signal transcription start AUG stop 5 3 exon 1 exon 2 exon 3

Answer 1

Great proportion of inherited genetic diseases in human beings are caused by premature stop codons. These pre mature stop codons can be degraded by Non sense mediated decay which is a mRNA surveillance pathway. But there is a certain rule of non sense mediated decay pathway to be efficient on premature stop codon. This is explained by the Exon junction complex model.

If the premature stop codon is located downstream of the last exon junction complex, the non sense mediated decay remains inefficient.

For the efficient non sense mediated decay the premature stop codon should be present at least 50 nucleotides upstream of the last exon junction. This is because the Exon junction complex will remain bound after the translation has terminated, hence termination factors interact with downstream exon junction complex which subsequently triggers Nonsense mediated decay.

Refer the following image for explanation. Figure 1 shows how NMD is not triggered and Figure 2 explains how NMD gets triggered.

Fiqure 1 PA Sigval stop AUG 3 exowl exon3 exon& Fiure Stop AUG exon3 exonl exona Date Premature Stop Cedon loated 5o ut upstreom o last exon triggering wall. Page No. NMD