Molecular Characteristics
Overview: SMG9 encodes a component of the SURF (SMG1, UPF1, and the eukaryotic release factors 1 and 3 [eRF1 and eRF3]) complex, which plays an important role in nonsense-mediated mRNA decay (NMD). This process protects the cell from the negative effects of truncated proteins through detecting and degrading transcripts containing premature stop codons (PTC).
Mechanism: NMD is a complex process that has been preserved in all eukaryotes studied to date. The current model suggests that a UPF2-UPF3B complex flags exon-exon junctions and will initiate a process that leads to the destruction of PTC-containing transcripts if encountered downstream of a stop codon. The most important step in this process involves the phosphorylation of UPF1 by SMG1, which requires the action of two proteins, SMG8 and SMG9, in the SURF complex. The SURF complex assembles on ribosomes that encounter a PTC. When phosphorylated, UPF1 recruits SMG5, SMG6, and SMG7, releases eRF1 and eRF3, and stops the translation of the mRNA. The PTC-containing mRNA is degraded through SMG5–SMG7-mediated exonucleolytic decay and SMG6-mediated endonucleolytic decay. NMD affects at least 10% of the human transcripts.
Mutations and pathophysiology
SMG9 is located at 19q13.31. A study identified a single disease locus and two independent, homozygous, loss-of-function mutations (c.520_521delCC and c.701+4A >G) involving SMG9. Deficiency of SMG9 in humans does not appear to impair NMD but does appear to cause a global transcriptional dysregulation in the affected cells. Global transcriptional profiling of affected individuals cells show a prevalent upregulation of gene expression, particularly in the genes involved in cellular movement, growth and proliferation, immune response, and cell death. However, genes responsible for lipid metabolism and tissue development process are downregulated.