Abstract
Telomere shortening induces a nonproliferative senescent phenotype, believed to reduce cancer risk, and telomeres are involved in a poorly understood manner in responses to DNA damage. Although telomere disruption induces p53 and triggers apoptosis or cell cycle arrest, the features of the disrupted telomere that trigger this response and the precise mechanism involved are poorly understood. Using human cells, we show that DNA oligonucleotides homologous to the telomere 3' overhang sequence specifically induce and activate p53 and activate an S phase checkpoint by modifying the Nijmegen breakage syndrome protein, known to mediate the S phase checkpoint after DNA damage. These responses are mediated, at least in part, by the ATM kinase and are not attributable to disruption of cellular telomeres. Based on these and earlier data, we propose that these oligonucleotides mimic a physiological signal, exposure of the telomere 3' overhang due to opening of the normal telomere loop structure, and hence evoke these protective antiproliferative responses in the absence of DNA damage or telomere disruption.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Ataxia Telangiectasia Mutated Proteins
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Base Sequence
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Cell Cycle / drug effects
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Cell Cycle / physiology
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / physiology*
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Cells, Cultured
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DNA / chemistry
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DNA / genetics
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DNA / pharmacology*
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DNA-Binding Proteins*
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E2F Transcription Factors
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Fibroblasts / cytology
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Fibroblasts / drug effects
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Fibroblasts / metabolism
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Humans
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Infant, Newborn
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Jurkat Cells
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Nuclear Proteins / genetics
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Nuclear Proteins / physiology*
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Nucleic Acid Conformation
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Oligonucleotides / genetics
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Oligonucleotides / pharmacology
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Phosphorylation
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Protein Serine-Threonine Kinases / metabolism
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S Phase / drug effects*
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S Phase / physiology
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Telomerase / genetics*
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Time Factors
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Transcription Factors / metabolism
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Tumor Cells, Cultured
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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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E2F Transcription Factors
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NBN protein, human
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Nuclear Proteins
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Oligonucleotides
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Transcription Factors
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Tumor Suppressor Protein p53
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Tumor Suppressor Proteins
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DNA
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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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Telomerase