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- W2920140715 abstract "2405 Replicative senescence is a natural barrier to cellular proliferation that is triggered by telomere erosion and dysfunction. Although it is recognized that the p53 and Rb pathways are critical for the induction and maintenance of replicative senescence, little is known about the sensors of telomere dysfunction that initiate the senescence response. ATM, the product of the gene that is mutated in the disorder ataxia telangiectasia, plays a critical role in the initiation of response pathways to ionizing radiation (IR). To assess whether ATM is activated during cellular aging and senescence, we used antibodies that specifically recognize the active, phosphorylated form of ATM. We found that whereas activated ATM was rarely observed in early-passage human fibroblasts, it was readily detected in late-passage fibroblasts. The ATM activation in late-passage cells was accompanied by accumulation of total p53 and p21 proteins and the formation of nuclear foci that contain phosphorylated ATM, NBS1, 53BP1, and H2AX-γ. Ectopic expression of telomerase in late-passage fibroblasts abrogated ATM activation, suggesting that the ATM activation resulted from telomere dysfunction. To ascertain whether telomere dysfunction-induced ATM activation requires chromosomal fusion-bridge-breakage cycles, we uncapped telomeres in quiescent, non-dividing cells using a lentivirus that expresses a dominant-inhibitory form of the telomere binding protein TRF2 (TRF2ΔBΔM). Transduction of TRF2ΔBΔM, but not a control TRF2 construct, into non-cycling cells activated ATM, indicating that telomere uncapping per se is sufficient for ATM activation. Although ATM activation was readily observed in pre-senescent cells, it disappeared with progression to senescence. However, ATM had the ability to be activated in senescent cells in response to IR, suggesting that the short telomeres of senescent cells are somehow shielded from initiating a signaling response. Together, these results are consistent with the idea that ATM activation contributes to the induction, but not the maintenance, of replicative senescence." @default.
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- W2920140715 date "2004-04-01" @default.
- W2920140715 modified "2023-09-27" @default.
- W2920140715 title "ATM activation is a marker of cellular aging and a precursor to replicative senescence." @default.
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