The mRNA surveillance protein hSMG-1 functions in genotoxic stress response pathways in mammalian cells

Mol Cell. 2004 Jun 4;14(5):585-98. doi: 10.1016/j.molcel.2004.05.005.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 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
  • RNA Helicases
  • RNA Stability / genetics*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism*
  • Radiation, Ionizing
  • 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

Substances

  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • RNA, Messenger
  • Trans-Activators
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • Protein Kinases
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Protein-Serine-Threonine Kinases
  • Metalloendopeptidases
  • O-sialoglycoprotein endopeptidase
  • RNA Helicases
  • UPF1 protein, human

Associated data

  • GENBANK/AF395444