title: The mRNA surveillance protein hSMG-1 functions in genotoxic stress response pathways in mammalian cells.
abstract: 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.
authors.affiliation: Program in Signal Transduction Research, The Burnham Institute, La Jolla, CA 92037, USA.
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Brumbaugh
authors.forename: Diane M
authors.initials: DM
authors.lastname: Otterness
authors.forename: Christoph
authors.initials: C
authors.lastname: Geisen
authors.forename: Vasco
authors.initials: V
authors.lastname: Oliveira
authors.forename: John
authors.initials: J
authors.lastname: Brognard
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Li
authors.forename: Fabrice
authors.initials: F
authors.lastname: Lejeune
authors.forename: Randal S
authors.initials: RS
authors.lastname: Tibbetts
authors.forename: Lynne E
authors.initials: LE
authors.lastname: Maquat
authors.forename: Robert T
authors.initials: RT
authors.lastname: Abraham
mesh_terms: D020816:Amino Acid Motifs / Q000502:physiology; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D004249:DNA Damage / Q000235:genetics* / Q000528:radiation effects; D004268:DNA-Binding Proteins; D042822:Genomic Instability / Q000235:genetics / Q000528:radiation effects; D006367:HeLa Cells; D006801:Humans; D008666:Metalloendopeptidases; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D020365:RNA Helicases; D020871:RNA Stability / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D011839:Radiation, Ionizing; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D011494:Protein Kinases; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D008666:Metalloendopeptidases; C070738:O-sialoglycoprotein endopeptidase; D020365:RNA Helicases; C101828:UPF1 protein, human