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首页> 外文期刊>Epigenetics & Chromatin >Both telomeric and non-telomeric DNA damage are determinants of mammalian cellular senescence
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Both telomeric and non-telomeric DNA damage are determinants of mammalian cellular senescence

机译：端粒和非端粒DNA损伤均是哺乳动物细胞衰老的决定因素

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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 γ-H2AX foci (γ-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 γ-foci and quantify the number of telomeric versus non-telomeric γ-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 γ-foci. Most notably, we report that, as human and mouse cells approach senescence, all cells exhibit similar numbers of total γ-foci per cell, irrespective of chromosomal locations. Conclusion Our results suggest that the chromosome location of senescence-related γ-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.
机译：背景细胞衰老是正常哺乳动物细胞在有限数量的细胞分裂后达到的状态，其特征是形态和生理变化，包括细胞周期的最终停滞。衰老对细胞分裂的限制可能在机体衰老和预防肿瘤发生中起重要作用。细胞衰老和生物衰老都伴随着DNA损伤的增加，这被视为形成了γ-H2AX病灶（γ-病灶），这可能是在未封端的端粒或DNA损伤的非端粒位点发现的。然而，从未证明端粒和非端粒相关的DNA损伤对诱导衰老的相对重要性。在这里，我们提出了一种新的方法，可以准确地确定γ病灶的染色体位置，并量化与人和小鼠细胞衰老相关的端粒对非端粒γ病灶的数量。这种方法使研究人员可以获得准确的值，并避免了早期方法固有的各种可能的错误估计。结果在中期染色体上使用结合的免疫荧光和端粒荧光原位杂交，我们显示人类细胞衰老不仅由端粒DNA损伤决定。另外，小鼠细胞衰老并不仅仅由非端粒DNA损伤决定。通过比较来自不同世代端粒酶无效小鼠的细胞与人类细胞，我们显示来自端粒酶无效小鼠的细胞，其端粒基本上很短，主要含有端粒γ病灶。最值得注意的是，我们报告说，随着人类和小鼠细胞接近衰老，所有细胞均显示出每个细胞类似数量的总γ病灶，而与染色体位置无关。结论我们的结果表明，与衰老相关的γ-焦点的染色体位置由端粒长度决定，而不是由物种本身决定。此外，我们的数据表明，端粒和非端粒DNA损伤反应在发出细胞衰老和机体衰老的信号中起着同等作用。这些数据对诱导或延迟不同物种细胞衰老的机制的研究具有重要意义。

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