Constricted migration increases DNA damage and independently represses cell cycle.
Constricted migration increases DNA damage and independently represses cell cycle.
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DOI：
10.1091/mbc.e18-02-0079
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发表时间：
2018-08-08
影响因子：
3.3
通讯作者：
Discher DE
中科院分区：
文献类型：
--
作者：
Pfeifer CR;Xia Y;Zhu K;Liu D;Irianto J;García VMM;Millán LMS;Niese B;Harding S;Deviri D;Greenberg RA;Discher DE
细胞通过致密组织或小毛细血管的迁移可以延长细胞核，甚至破坏细胞核，对细胞周期的任何影响都有可能影响包括致癌在内的各种过程。在这里，核破裂和DNA损伤的增加与收缩迁移在不同阶段的细胞周期，我们表明是部分抑制。我们研究了几种接触抑制或不接触抑制的癌细胞系，这些癌细胞系在通过小孔迁移后表现出不同的核纤层破裂频率。DNA修复因子在迁移后总是错误定位，并且过量的DNA损伤明显表现为磷酸活化的ATM和γH2AX的泛核浆灶。如有丝分裂检查点所预期的，病灶计数在细胞周期晚期受到抑制，并且接触抑制细胞通过大孔迁移到稀疏微环境中也如预期的那样导致细胞周期重新进入，并且对基础水平的损伤病灶没有影响。收缩孔延迟这种再入，而多余的病灶发生独立的细胞周期阶段。敲除修复因子增加DNA损伤独立于细胞周期，与收缩迁移的影响一致。由于这种迁移会导致DNA损伤并阻碍增殖，因此它说明了癌细胞的命运选择是“去或生长”。
Cell migration through dense tissues or small capillaries can elongate the nucleus and even damage it, and any impact on cell cycle has the potential to affect various processes including carcinogenesis. Here, nuclear rupture and DNA damage increase with constricted migration in different phases of cell cycle—which we show is partially repressed. We study several cancer lines that are contact inhibited or not and that exhibit diverse frequencies of nuclear lamina rupture after migration through small pores. DNA repair factors invariably mislocalize after migration, and an excess of DNA damage is evident as pan-nucleoplasmic foci of phosphoactivated ATM and γH2AX. Foci counts are suppressed in late cell cycle as expected of mitotic checkpoints, and migration of contact-inhibited cells through large pores into sparse microenvironments leads also as expected to cell-cycle reentry and no effect on a basal level of damage foci. Constricting pores delay such reentry while excess foci occur independent of cell-cycle phase. Knockdown of repair factors increases DNA damage independent of cell cycle, consistent with effects of constricted migration. Because such migration causes DNA damage and impedes proliferation, it illustrates a cancer cell fate choice of “go or grow.”