Abstract
Primary human cells in culture invariably stop dividing and enter a state of growth arrest called replicative senescence. This transition is induced by programmed telomere shortening, but the underlying mechanisms are unclear. Here, we report that overexpression of TRF2, a telomeric DNA binding protein, increased the rate of telomere shortening in primary cells without accelerating senescence. TRF2 reduced the senescence setpoint, defined as telomere length at senescence, from 7 to 4 kilobases. TRF2 protected critically short telomeres from fusion and repressed chromosome-end fusions in presenescent cultures, which explains the ability of TRF2 to delay senescence. Thus, replicative senescence is induced by a change in the protected status of shortened telomeres rather than by a complete loss of telomeric DNA.
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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Antigens, Polyomavirus Transforming / genetics
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Antigens, Polyomavirus Transforming / metabolism
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Cell Division*
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Cell Line
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Cells, Cultured
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Cellular Senescence*
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DNA / metabolism*
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Humans
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Oncogene Proteins, Viral / genetics
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Oncogene Proteins, Viral / metabolism
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Papillomavirus E7 Proteins
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Repressor Proteins*
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Retinoblastoma Protein / metabolism
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Retroviridae / genetics
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Telomere / metabolism
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Telomere / physiology*
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Telomeric Repeat Binding Protein 2
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Transformation, Genetic
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Tumor Suppressor Protein p53 / metabolism
Substances
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Antigens, Polyomavirus Transforming
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DNA-Binding Proteins
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E6 protein, Human papillomavirus type 16
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Oncogene Proteins, Viral
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Papillomavirus E7 Proteins
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Repressor Proteins
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Retinoblastoma Protein
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Telomeric Repeat Binding Protein 2
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Tumor Suppressor Protein p53
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oncogene protein E7, Human papillomavirus type 16
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DNA