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Both Complexity and Location of DNA Damage Contribute to Cellular Senescence Induced by Ionizing Radiation.

ABSTRACT: Persistent DNA damage is considered as a main cause of cellular senescence induced by ionizing radiation. However, the molecular bases of the DNA damage and their contribution to cellular senescence are not completely clear. In this study, we found that both heavy ions and X-rays induced senescence in human uveal melanoma 92-1 cells. By measuring senescence associated-?-galactosidase and cell proliferation, we identified that heavy ions were more effective at inducing senescence than X-rays. We observed less efficient repair when DNA damage was induced by heavy ions compared with X-rays and most of the irreparable damage was complex of single strand breaks and double strand breaks, while DNA damage induced by X-rays was mostly repaired in 24 hours and the remained damage was preferentially associated with telomeric DNA. Our results suggest that DNA damage induced by heavy ion is often complex and difficult to repair, thus presents as persistent DNA damage and pushes the cell into senescence. In contrast, persistent DNA damage induced by X-rays is preferentially associated with telomeric DNA and the telomere-favored persistent DNA damage contributes to X-rays induced cellular senescence. These findings provide new insight into the understanding of high relative biological effectiveness of heavy ions relevant to cancer therapy and space radiation research.

SUBMITTER: Zhang X

PROVIDER: S-EPMC4871470 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Both Complexity and Location of DNA Damage Contribute to Cellular Senescence Induced by Ionizing Radiation.

Zhang Xurui X Ye Caiyong C Sun Fang F Wei Wenjun W Hu Burong B Wang Jufang J

PloS one 20160517 5

Persistent DNA damage is considered as a main cause of cellular senescence induced by ionizing radiation. However, the molecular bases of the DNA damage and their contribution to cellular senescence are not completely clear. In this study, we found that both heavy ions and X-rays induced senescence in human uveal melanoma 92-1 cells. By measuring senescence associated-β-galactosidase and cell proliferation, we identified that heavy ions were more effective at inducing senescence than X-rays. We ...[more]

PMID: 27187621

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Project description:BACKGROUND: Cellular senescence is a state reached by normal mammalian cells after a finite number of cell divisions and is characterized by morphological and physiological changes including terminal cell-cycle arrest. The limits on cell division imposed by senescence may play an important role in both organismal aging and in preventing tumorigenesis. Cellular senescence and organismal aging are both accompanied by increased DNA damage, seen as the formation of gamma-H2AX foci (gamma-foci), which may be found on uncapped telomeres or at non-telomeric sites of DNA damage. However, the relative importance of telomere- and non-telomere-associated DNA damage to inducing senescence has never been demonstrated. Here we present a new approach to determine accurately the chromosomal location of gamma-foci and quantify the number of telomeric versus non-telomeric gamma-foci associated with senescence in both human and mouse cells. This approach enables researchers to obtain accurate values and to avoid various possible misestimates inherent in earlier methods. RESULTS: Using combined immunofluorescence and telomere fluorescence in situ hybridization on metaphase chromosomes, we show that human cellular senescence is not solely determined by telomeric DNA damage. In addition, mouse cellular senescence is not solely determined by non-telomeric DNA damage. By comparing cells from different generations of telomerase-null mice with human cells, we show that cells from late generation telomerase-null mice, which have substantially short telomeres, contain mostly telomeric gamma-foci. Most notably, we report that, as human and mouse cells approach senescence, all cells exhibit similar numbers of total gamma-foci per cell, irrespective of chromosomal locations. CONCLUSION: Our results suggest that the chromosome location of senescence-related gamma-foci is determined by the telomere length rather than species differences per se. In addition, our data indicate that both telomeric and non-telomeric DNA damage responses play equivalent roles in signaling the initiation of cellular senescence and organismal aging. These data have important implications in the study of mechanisms to induce or delay cellular senescence in different species.

Dataset Information

Both Complexity and Location of DNA Damage Contribute to Cellular Senescence Induced by Ionizing Radiation.

Publications

Both Complexity and Location of DNA Damage Contribute to Cellular Senescence Induced by Ionizing Radiation.

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