Mechanosensing by the Lamina Protects against Nuclear Rupture, DNA Damage, and Cell-Cycle Arrest
Mechanosensing by the Lamina Protects against Nuclear Rupture, DNA Damage, and Cell-Cycle Arrest
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DOI：
10.1016/j.devcel.2019.04.020
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发表时间：
2019-06-17
影响因子：
11.8
通讯作者：
Discher, Dennis E.
中科院分区：
文献类型：
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作者：
Cho, Sangkyun;Vashisth, Manasvita;Discher, Dennis E.
细胞力或细胞外基质（ECM）是否会影响基因组完整性在很大程度上尚不清楚。在这里，急性扰动（类似于1小时）肌动球蛋白应力或ECM弹性引起层粘连蛋白A，DNA损伤和细胞周期的快速和可逆的变化。这些发现与心脏等器官特别相关，因为DNA损伤在出生后不久就永久性地阻止了心肌细胞的增殖，从而消除了包括心脏病发作在内的损伤后的再生。胚胎心脏、心脏分化的iPS细胞（诱导多能干细胞）和各种非肌肉细胞类型都表明，肌动球蛋白驱动的核破裂会导致DNA修复因子的细胞质错误定位和过量的DNA损伤。双核和微核随着端粒缩短而增加，这都有利于细胞周期停滞。层粘连蛋白A和修复因子的缺陷加剧了这些影响，但层粘连蛋白A相关的缺陷被修复因子过表达和收缩调节剂在临床试验中挽救。刚性ECM上的收缩细胞通常表现出低磷酸化和基质金属蛋白酶-2（MMP 2）对层粘连蛋白-A的缓慢降解，并且抑制这种层粘连蛋白-A周转和肌动球蛋白收缩性可以使DNA损伤最小化。因此，Lamin-A是应力稳定的，以机械保护基因组。
Whether cell forces or extracellular matrix (ECM) can impact genome integrity is largely unclear. Here, acute perturbations (similar to 1 h) to actomyosin stress or ECM elasticity cause rapid and reversible changes in lamin-A, DNA damage, and cell cycle. The findings are especially relevant to organs such as the heart because DNA damage permanently arrests cardio-myocyte proliferation shortly after birth and thereby eliminates regeneration after injury including heart attack. Embryonic hearts, cardiac-differentiated iPS cells (induced pluripotent stem cells), and various nonmuscle cell types all show that actomyosin-driven nuclear rupture causes cytoplasmic mis-localization of DNA repair factors and excess DNA damage. Binucleation and micronuclei increase as telomeres shorten, which all favor cell-cycle arrest. Deficiencies in lamin-A and repair factors exacerbate these effects, but lamin-A-associated defects are rescued by repair factor overexpression and also by contractility modulators in clinical trials. Contractile cells on stiff ECM normally exhibit low phosphorylation and slow degradation of lamin-A by matrixmetalloprotease-2 (MMP2), and inhibition of this lamin-A turnover and also actomyosin contractility are seen to minimize DNA damage. Lamin-A is thus stress stabilized to mechano-protect the genome.