p19(Arf) is required for the cellular response to chronic DNA damage.
p19(Arf) is required for the cellular response to chronic DNA damage.
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DOI：
10.1038/onc.2015.490
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发表时间：
2016-08-18
期刊：
影响因子：
8
通讯作者：
Attardi LD
中科院分区：
文献类型：
--
作者：
Bieging-Rolett KT;Johnson TM;Brady CA;Beaudry VG;Pathak N;Han S;Attardi LD
p53肿瘤抑制因子是一种应激传感器，响应DNA损伤或致癌信号而驱动细胞周期停滞或凋亡。p53激活的致癌信号依赖于p19 Arf肿瘤抑制，而p53激活下游的急性DNA损伤的报道是p19 Arf独立的。因此，p19 Arf缺陷型小鼠胚胎成纤维细胞（MEFs）响应于急性DNA损伤而停滞。然而，p19 Arf是复制性衰老所必需的，这是一种与激活的DNA损伤反应相关的条件，因为p19 Arf −/− MEFs在连续传代后不会衰老。p19 Arf这些看似不同的作用的一个可能的解释是，急性和慢性DNA损伤反应是不同的机制。复制性衰老可能是由慢性低剂量DNA损伤反应引起的，其中p19 Arf具有特定的作用。因此，我们研究了p19 Arf在细胞对慢性低剂量DNA损伤剂处理的反应中的作用，通过将MEFs维持在低氧环境中，每天给予0.5戈伊γ射线照射或150μM羟基脲（复制应激诱导剂）。与它们对急性DNA损伤的反应相反，暴露于慢性DNA损伤的p19 Arf −/− MEFs不会衰老，揭示了p19 Arf在低水平慢性DNA损伤衰老中的选择性作用。我们进一步表明，p19 Arf −/− MEFs暴露于慢性DNA损伤中的p53通路活化相对于野生型MEFs减弱，表明p19 Arf在微调p53活性中的作用。然而，联合Nutlin 3a和慢性DNA损伤剂治疗不足以促进p19 Arf −/− MEFs的衰老，这表明p19 Arf在慢性DNA损伤反应中的作用可能部分是p53非依赖性的。这些数据表明，p19 Arf的细胞反应的重要性，在文化或癌基因表达后发生的低水平的DNA损伤，提供了新的见解如何p19 Arf作为一种肿瘤抑制剂。此外，我们的研究有助于协调报告表明p19 Arf和DNA损伤信号通路在肿瘤抑制中的关键作用。
The p53 tumor suppressor is a stress sensor, driving cell-cycle arrest or apoptosis in response to DNA damage or oncogenic signals. p53 activation by oncogenic signals relies on the p19Arf tumor suppressor, while p53 activation downstream of acute DNA damage is reported to be p19Arf-independent. Accordingly, p19Arf-deficient mouse embryo fibroblasts (MEFs) arrest in response to acute DNA damage. However, p19Arf is required for replicative senescence, a condition associated with an activated DNA damage response, as p19Arf−/− MEFs do not senesce after serial passage. A possible explanation for these seemingly disparate roles for p19Arf is that acute and chronic DNA damage responses are mechanistically distinct. Replicative senescence may result from chronic, low-dose DNA damage responses in which p19Arf has a specific role. We therefore examined the role of p19Arf in cellular responses to chronic, low-dose DNA damaging agent treatment by maintaining MEFs in low oxygen and administering 0.5 Gy γ-irradiation daily or 150μM hydroxyurea, a replication stress-inducer. In contrast to their response to acute DNA damage, p19Arf−/− MEFs exposed to chronic DNA damage do not senesce, revealing a selective role for p19Arf in senescence upon low-level, chronic DNA damage. We show further that p53 pathway activation in p19Arf−/− MEFs exposed to chronic DNA damage is attenuated relative to wild-type MEFs, suggesting a role for p19Arf in fine-tuning p53 activity. However, combined Nutlin3a and chronic DNA damaging agent treatment is insufficient to promote senescence in p19Arf−/− MEFs, suggesting that the role of p19Arf in the chronic DNA damage response may be partially p53-independent. These data suggest the importance of p19Arf for the cellular response to the low-level DNA damage incurred in culture or upon oncogene expression, providing new insight into how p19Arf serves as a tumor suppressor. Moreover, our study helps reconcile reports suggesting crucial roles for both p19Arf and DNA damage signaling pathways in tumor suppression.