The mRNA Surveillance Protein hSMG-1 Functions in Genotoxic Stress Response Pathways in Mammalian Cells

• Published in: Molecular cell Vol. 14; no. 5; pp. 585 - 598
• Main Authors: Brumbaugh, Kathryn M., Otterness, Diane M., Geisen, Christoph, Oliveira, Vasco, Brognard, John, Li, Xiaojie, Lejeune, Fabrice, Tibbetts, Randal S., Maquat, Lynne E., Abraham, Robert T.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 04.06.2004
• Subjects: Amino Acid Motifs - physiology; Ataxia Telangiectasia Mutated Proteins; Cell Cycle Proteins; DNA Damage - genetics; DNA Damage - radiation effects; DNA-Binding Proteins; Genomic Instability - genetics; Genomic Instability - radiation effects; HeLa Cells; Humans; Metalloendopeptidases; Molecular Sequence Data; Phosphorylation; Protein Kinases - genetics; Protein Kinases - metabolism; Protein Kinases - physiology; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Radiation, Ionizing; RNA Stability - genetics; RNA, Messenger - genetics; RNA, Messenger - metabolism; Trans-Activators - genetics; Trans-Activators - metabolism; Transcription, Genetic - genetics; Transcription, Genetic - radiation effects; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumor Suppressor Proteins
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2004.05.005

Members of the PI 3-kinase-related kinase (PIKK) family function in mitogenic and stress-induced signaling pathways in eukaryotic cells. Here, we characterize the newest PIKK family member, hSMG-1, as a genotoxic stress-activated protein kinase that displays some functional overlap with the related kinase, ATM, in human cells. Both ATM and hSMG-1 phosphorylate Ser/Thr-Gln-containing target sequences in the checkpoint protein p53 and the nonsense-mediated mRNA decay (NMD) protein hUpf1. Expression of hSMG-1 is required for optimal p53 activation after cellular exposure to genotoxic stress, and depletion of hSMG-1 leads to spontaneous DNA damage and increased sensitivity to ionizing radiation (IR). Moreover, IR exposure triggers hUpf1 phosphorylation at Ser/Thr-Gln motifs, and both ATM and hSMG-1 contribute to these phosphorylation events. Finally, NMD is suppressed in hSMG-1- but not ATM-deficient cells. These results indicate that hSMG-1 plays important roles in the maintenance of both genome and transcriptome integrity in human cells.