Abstract
Different levels or types of DNA damage activate distinct signaling pathways that elicit various cellular responses, including cell-cycle arrest, DNA repair, senescence, and apoptosis. Whereas a range of DNA-damage responses have been characterized, mechanisms underlying subsequent cell-fate decision remain elusive. Here we exposed cultured cells and mice to different doses and dose rates of γ-irradiation, which revealed cell-type-specific sensitivities to chronic, but not acute, γ-irradiation. Among tested cell types, human fibroblasts were associated with the highest levels of growth inhibition in response to chronic γ-irradiation. In this context, fibroblasts exhibited a reversible G1 cell-cycle arrest or an irreversible senescence-like growth arrest, depending on the irradiation dose rate or the rate of DNA damage. Remarkably, when the same dose of γ-irradiation was delivered chronically or acutely, chronic delivery induced considerably more cellular senescence. A similar effect was observed with primary cells isolated from irradiated mice. We demonstrate a critical role for the ataxia telangiectasia mutated (ATM)/tumor protein p53 (TP53)/p21 pathway in regulating DNA-damage-associated cell fate. Indeed, blocking the ATM/TP53/p21 pathway deregulated DNA damage responses, leading to micronucleus formation in chronically irradiated cells. Together these results provide insights into the mechanisms governing cell-fate determination in response to different rates of DNA damage.
Highlights
Lesions to genomic DNA, including modified bases, and singleand double-strand breaks, are constantly generated in living cells under physiological and environmental conditions [1]
Cells from patients with Ataxia-telangiectasia or Nijmegen breakage syndrome are sensitive to ionizing radiation because a protein required for DNA damage responses is dysfunctional in these patients [15]
Sustained DNA damage causes individual cells to adopt a wider range of cell fates, including apoptosis, DNA-damage tolerance, or proliferation
Summary
Lesions to genomic DNA, including modified bases, and singleand double-strand breaks, are constantly generated in living cells under physiological and environmental conditions [1]. DNA damage can result from internal or external sources and cause mutations to genomic DNA. The overall rate of spontaneous DNA damage in human cells is estimated to be tens of thousands of events per day, which is approximately equivalent to the rate induced by exposure to sparsely ionizing radiation (1.5– 2.0 Gray (Gy)/day) [3,4]. Under these conditions, individual cells adopt particular cell fates to maintain homeostasis within the living organisms. As cell fates elicited by DNA damage responses may impact aging and age-associated diseases, it is important to understand the mechanisms governing DNA-damage associated cell-fate decisions
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