Key Points
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Cells respond to the perception of DNA damage by arresting cell-cycle progression and attempting repair: collectively these actions are known as the DNA-damage response (DDR). In mammals, proliferation is not resumed until DNA damage is fixed.
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Cellular senescence is a condition in which cells, despite being alive, are unable to proliferate further. This is a stress response, and therefore is different from quiescence or terminal differentiation.
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Replicative senescence limits the proliferation of normal human cells. Proliferation that is associated with progressive telomere shortening leads to senescence establishment when critically short telomeres are recognized as DNA damage and trigger a DDR.
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Mammalian ageing is associated with the progressive accumulation of senescent cells and DDR accumulation in stem or progenitor cells and more differentiated cells. In the skin of primates, DDR markers associate with the telomeres.
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Oncogene activation also causes DDR activation and cellular senescence. Oncogene-induced DNA damage is caused by altered DNA replication, and oncogene-induced senescence is a barrier to cancer. Senescent cells can be observed in vivo in preneoplastic lesions.
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Collectively, mounting evidence indicates that senescence, triggered by different stimuli, is the outcome of a protracted DDR.
Abstract
Cellular senescence is associated with ageing and cancer in vivo and has a proven tumour-suppressive function. Common to both ageing and cancer is the generation of DNA damage and the engagement of the DNA-damage response pathways. In this Review, the diverse mechanisms that lead to DNA-damage generation and the activation of DNA-damage-response signalling pathways are discussed, together with the evidence for their contribution to the establishment and maintenance of cellular senescence in the context of organismal ageing and cancer development.
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Acknowledgements
F.d'A.d.F. is supported by the Associazione Italiana per la Ricerca sul Cancro, the Association for International Cancer Research, the Human Frontier Science Program, the FP6 and FP7 program of the European Union and the EMBO Young Investigator Program.
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d'Adda di Fagagna, F. Living on a break: cellular senescence as a DNA-damage response. Nat Rev Cancer 8, 512–522 (2008). https://doi.org/10.1038/nrc2440
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DOI: https://doi.org/10.1038/nrc2440
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