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
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Motifs / physiology
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Ataxia Telangiectasia Mutated Proteins
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Cell Cycle Proteins
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DNA Damage / genetics*
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DNA Damage / radiation effects
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DNA-Binding Proteins
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Genomic Instability / genetics
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Genomic Instability / radiation effects
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HeLa Cells
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Humans
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Metalloendopeptidases
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Molecular Sequence Data
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Phosphorylation
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Protein Kinases / genetics
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Protein Kinases / metabolism
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Protein Kinases / physiology*
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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RNA Helicases
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RNA Stability / genetics*
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RNA, Messenger / genetics
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RNA, Messenger / metabolism*
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Radiation, Ionizing
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Trans-Activators / genetics
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Trans-Activators / metabolism
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Transcription, Genetic / genetics
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Transcription, Genetic / radiation effects
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism
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Tumor Suppressor Proteins
Substances
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Cell Cycle Proteins
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DNA-Binding Proteins
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RNA, Messenger
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Trans-Activators
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Tumor Suppressor Protein p53
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Tumor Suppressor Proteins
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Protein Kinases
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ATM protein, human
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Ataxia Telangiectasia Mutated Proteins
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Protein Serine-Threonine Kinases
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Metalloendopeptidases
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O-sialoglycoprotein endopeptidase
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RNA Helicases
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UPF1 protein, human