Sci. STKE, 11 September 2001
mRNA Control Measure Twice, Cut Once
Genes contain both exons, which encode the amino acid sequence, and introns, which do not. The latter must be removed from the pre-messenger RNA (mRNA) transcript with great exactitude--a single base error may result in premature termination of translation as a consequence of a shift in reading frame. In order to guard against synthesizing truncated and potentially deleterious proteins, a multisubunit complex is used to "mark" the place where exons have been joined. If translation terminates upstream of any such mark, then the mRNA is shunted into a degradation pathway called nonsense-mediated decay (NMD). Kim et al. and Lykke-Andersen et al. now provide the first evidence for physical interaction between components of the mark and those of NMD. In a related paper, Yamashita et al. have cloned and characterized SMG-1, a human protein involved in NMD. Human SMG-1, a member of the phosphatidylinositol 3-kinase-related protein kinase family, was phosphorylated in vitro and could phosphorylate at least one other protein involved in NMD, hUPF1/SMG-2. In human cells expressing wild-type SMG-1 and an aberrantly spliced β-globin mRNA, amounts of the mutant β-globin mRNA were greatly reduced, whereas in cells expressing kinase-defective SMG-1 and aberrantly spliced β-globin mRNA, amounts of the mutant β-globin mRNA were increased. These findings suggest that SMG-1 plays a role in NMD in human cells. Based on other experiments showing that the inhibition of SMG-1 allowed for accumulation of aberrantly spliced p53 transcripts, the authors suggest an interesting therapeutic strategy: blocking NMD by inhibiting SMG-1 might help ameliorate disorders. For example, inhibiting NMD in cells containing mutant p53 that has weaker than normal activity would allow weaker activity, which is better than none at all.
J. Lykke-Andersen, M.-D. Shu, J. A. Steitz, Communication of the position of exon-exon junctions to the mRNA surveillance machinery by the protein RNPS1. Science 293, 1836-1839 (2001). [Abstract] [Full Text]
A. Yamashita, T. Ohnishi, I. Kashima, Y. Taya, S. Ohno, Human SMG-1, a novel phosphatidylinositol 3-kinase-related protein kinase, associates with components of the mRNA surveillance complex and is involved in the regulation of nonsense-mediated mRNA decay. Genes Dev. 15, 2215-2228 (2001). [Abstract] [Full Text]
Citation: Measure Twice, Cut Once. Sci. STKE 2001, tw326 (2001).
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