RCC1-dependent activation of Ran accelerates cell cycle and DNA repair, inhibiting DNA damage-induced cell senescence.
RCC1-dependent activation of Ran accelerates cell cycle and DNA repair, inhibiting DNA damage-induced cell senescence.
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DOI：
10.1091/mbc.e16-01-0025
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发表时间：
2016-04-15
影响因子：
3.3
通讯作者：
Kalab P
中科院分区：
文献类型：
--
作者：
Cekan P;Hasegawa K;Pan Y;Tubman E;Odde D;Chen JQ;Herrmann MA;Kumar S;Kalab P
细胞周期和DNA修复涉及需要RanGTP调节的核质转运（NCT）的步骤。通过RCC1（Ran的鸟嘌呤核苷酸交换因子）过表达激活NCT加速了细胞周期和DNA修复。过表达RCC1的正常细胞逃避DNA损伤诱导的衰老，模仿具有高水平RCC1的癌细胞。细胞周期进程与DNA损伤修复的协调支持分裂细胞的基因组完整性。参与DNA损伤反应（DDR）和细胞周期的许多因子的功能依赖于它们的Ran GTP酶调节的核质转运（NCT）。由RCC1（Ran的鸟嘌呤核苷酸交换因子）介导的Ran与GTP的负载对于NCT活性至关重要。然而，RCC1或Ran β GTP在促进细胞增殖或DDR中的作用尚不清楚。我们发现，RCC1在正常细胞中的过表达增加了细胞的Ran β GTP水平，并加速了细胞周期和DNA损伤修复。结果，正常细胞过度表达RCC1逃避DNA损伤诱导的细胞周期停滞和衰老，模仿具有高内源性RCC1水平的结直肠癌细胞。RCC1诱导的衰老抑制需要Ran和exportin 1，并涉及53BP 1（一种大型NCT货物）的importin β依赖性核输入的激活。我们的研究结果表明，Ran β GTP调节的NCT活性的变化调节细胞周期的速率和DNA修复的效率。通过RCC1在调节细胞Ran β GTP水平和NCT中的重要作用，RCC1表达使维持DNA损伤的细胞增殖成为可能。
Cell cycle and DNA repair involve steps requiring RanGTP-regulated nuclear-cytoplasmic transport (NCT). The activation of NCT via overexpression of RCC1 (the guanine nucleotide exchange factor for Ran) accelerated the cell cycle and DNA repair. Normal cells overexpressing RCC1 evaded DNA damage–induced senescence, mimicking cancer cells with high levels of RCC1. The coordination of cell cycle progression with the repair of DNA damage supports the genomic integrity of dividing cells. The function of many factors involved in DNA damage response (DDR) and the cell cycle depends on their Ran GTPase–regulated nuclear–cytoplasmic transport (NCT). The loading of Ran with GTP, which is mediated by RCC1, the guanine nucleotide exchange factor for Ran, is critical for NCT activity. However, the role of RCC1 or Ran⋅GTP in promoting cell proliferation or DDR is not clear. We show that RCC1 overexpression in normal cells increased cellular Ran⋅GTP levels and accelerated the cell cycle and DNA damage repair. As a result, normal cells overexpressing RCC1 evaded DNA damage–induced cell cycle arrest and senescence, mimicking colorectal carcinoma cells with high endogenous RCC1 levels. The RCC1-induced inhibition of senescence required Ran and exportin 1 and involved the activation of importin β–dependent nuclear import of 53BP1, a large NCT cargo. Our results indicate that changes in the activity of the Ran⋅GTP–regulated NCT modulate the rate of the cell cycle and the efficiency of DNA repair. Through the essential role of RCC1 in regulation of cellular Ran⋅GTP levels and NCT, RCC1 expression enables the proliferation of cells that sustain DNA damage.