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Genes & Dev. 15 (17): 2215-2228

Copyright © 2001 by Cold Spring Harbor Laboratory Press.

Vol. 15, No. 17, pp. 2215-2228, September 1, 2001

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

Akio Yamashita,1,3 Tetsuo Ohnishi,1,3 Isao Kashima,1 Yoichi Taya,2 and Shigeo Ohno1,4

1 Department of Molecular Biology, Yokohama City University School of Medicine, Yokohama 236-0004, Japan; 2 Biology Division, National Cancer Center Research Institute, Tokyo 104-0045, Japan

Nonsense-mediated mRNA decay (NMD) is a conserved surveillance mechanism that eliminates imperfect mRNAs that contain premature translation termination codons (PTCs) and code for nonfunctional or potentially harmful polypeptides. We show that a novel phosphatidylinositol 3-kinase-related protein kinase, hSMG-1, is a human ortholog of a product of Caenorhabditis elegans smg-1, one of seven smg genes involved in NMD. hSMG-1 phosphorylates hUPF1/SMG-2 in vivo and in vitro at specific serine residues in SQ motifs. hSMG-1 can associate with hUPF1/SMG-2 and other components of the surveillance complex. In particular, overexpression of a kinase-deficient point mutant of hSMG-1, hSMG-1-DA, results in a marked suppression of the PTC-dependent beta -globin mRNA degradation; whereas that of wild-type hSMG-1 enhances it. We also show that inhibitors of hSMG-1 induce the accumulation of truncated p53 proteins in human cancer cell lines with p53 PTC mutation. Taken together, we conclude that hSMG-1 plays a critical role in NMD through the direct phosphorylation of hUPF1/SMG-2 in the evolutionally conserved mRNA surveillance complex.

[Key Words: NMD; PIK-related-protein kinase; smg; upf; PTC; p53]

3 These authors contributed equally to this work.

4 Corresponding author.

GENES & DEVELOPMENT 15:2215-2228 © 2001 by Cold Spring Harbor Laboratory Press  ISSN 0890-9369/01 $5.00

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