p53- and ATM-dependent apoptosis induced by telomeres lacking TRF2.
Although broken chromosomes can induce apoptosis, natural chromosome ends (telomeres) do not trigger this response. It is shown that this suppression of apoptosis involves the telomeric-repeat binding factor 2 (TRF2). Inhibition of TRF2 resulted in apoptosis in a subset of mammalian cell types. The response was mediated by p53 and the ATM (ataxia telangiectasia mutated) kinase, consistent with activation of a DNA damage checkpoint. Apoptosis was not due to rupture of dicentric chromosomes formed by end-to-end fusion, indicating that telomeres lacking TRF2 directly signal apoptosis, possibly because they resemble damaged DNA. Thus, in some cells, telomere shortening may signal cell death rather than senescence.
Laboratory for Cell Biology and Genetics, The Rockefeller University, New York, NY 10021, USA. Cell Genesys, Foster City, CA 94405, USA.
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Karlseder
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Broccoli
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Dai
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Hardy
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de Lange
D000256:Adenoviridae / Q000235:genetics / Q000502:physiology; D000818:Animals; D017209:Apoptosis; D001260:Ataxia Telangiectasia / Q000473:pathology; D064007:Ataxia Telangiectasia Mutated Proteins; D001402:B-Lymphocytes / Q000166:cytology; D018797:Cell Cycle Proteins; D002460:Cell Line; D002478:Cells, Cultured; D003001:Cloning, Molecular; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D005822:Genetic Vectors; D006801:Humans; D020287:In Situ Nick-End Labeling; D051379:Mice; D008938:Mitosis; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011506:Proteins / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology; D016615:Telomere / Q000502:physiology*; D035341:Telomeric Repeat Binding Protein 2; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D011506:Proteins; D035341:Telomeric Repeat Binding Protein 2; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases