p53 动力学的转变标志着逃避 DSB 诱导的细胞周期阻滞的细胞。
A Switch in p53 Dynamics Marks Cells That Escape from DSB-Induced Cell Cycle Arrest.
机构信息
Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA; Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
出版信息
Cell Rep. 2020 Aug 4;32(5):107995. doi: 10.1016/j.celrep.2020.107995.
Cellular responses to stimuli can evolve over time, resulting in distinct early and late phases in response to a single signal. DNA damage induces a complex response that is largely orchestrated by the transcription factor p53, whose dynamics influence whether a damaged cell will arrest and repair the damage or will initiate cell death. How p53 responses and cellular outcomes evolve in the presence of continuous DNA damage remains unknown. Here, we have found that a subset of cells switches from oscillating to sustained p53 dynamics several days after undergoing damage. The switch results from cell cycle progression in the presence of damaged DNA, which activates the caspase-2-PIDDosome, a complex that stabilizes p53 by inactivating its negative regulator MDM2. This work defines a molecular pathway that is activated if the canonical checkpoints fail to halt mitosis in the presence of damaged DNA.
细胞对刺激的反应可以随时间演变，导致对单个信号的反应出现明显的早期和晚期阶段。DNA 损伤会引发一种复杂的反应，主要由转录因子 p53 来协调，其动态变化会影响受损细胞是停止并修复损伤，还是启动细胞死亡。在持续的 DNA 损伤下，p53 反应和细胞结果如何演变尚不清楚。在这里，我们发现，在经历损伤数天后，一部分细胞会从 p53 的振荡动力学转变为持续的动力学。这种转变是由于受损 DNA 存在时细胞周期的进展，激活了半胱天冬酶-2-PIDDosome，这是一种通过失活其负调节因子 MDM2 来稳定 p53 的复合物。这项工作定义了一种分子途径，如果经典的检查点在存在受损 DNA 的情况下未能阻止有丝分裂，该途径就会被激活。
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