Nuclear rupture at sites of high curvature compromises retention of DNA repair factors.
Nuclear rupture at sites of high curvature compromises retention of DNA repair factors.
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DOI：
10.1083/jcb.201711161
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发表时间：
2018-11-05
期刊：
影响因子：
--
通讯作者：
Discher DE
中科院分区：
文献类型：
--
作者：
Xia Y;Ivanovska IL;Zhu K;Smith L;Irianto J;Pfeifer CR;Alvey CM;Ji J;Liu D;Cho S;Bennett RR;Liu AJ;Greenberg RA;Discher DE
夏等人展示测力探头和细胞骨架应力如何导致特定于细胞核的破裂。破裂与核曲率有关，低层蛋白A、高肌动球蛋白应力和僵硬的ECM促进了破裂。断裂导致DNA修复因子在细胞质中的错位。细胞核在物理上与细胞骨架、粘连和细胞外基质联系在一起--所有这些都支持力量，但它们与DNA损伤的关系尚不清楚。我们发现，多种DNA修复因子胞质错位的核破裂与外部探针或细胞附着在排列的胶原纤维或僵硬的基质上造成的高核曲率有关。层蛋白A的缺失极大地增强了定位错误，需要数小时的核再入，并与DNA损伤标记γH2AX的泛核质焦点的增加有关。在断裂的细胞核中，过量的DNA损伤可以通过多种DNA修复因子的共表达以及软基质或肌动球蛋白张力的抑制来挽救。收缩能力增强则相反，层蛋白A低的僵硬肿瘤确实表现出更多的核弯曲，更频繁的核破裂和过度的DNA损伤。额外的压力可能起到一定作用，但数据表明，高曲率会导致核破裂，这会损害DNA修复因素的保留，并有利于持续的损伤。
Xia et al. show how force probes and cytoskeletal stress can induce nucleus-specific rupture. Rupture correlates with nuclear curvature and is promoted by low lamin A, high actomyosin stress, and stiff ECM. Rupture leads to cytoplasmic mislocalization of DNA repair factors. The nucleus is physically linked to the cytoskeleton, adhesions, and extracellular matrix—all of which sustain forces, but their relationships to DNA damage are obscure. We show that nuclear rupture with cytoplasmic mislocalization of multiple DNA repair factors correlates with high nuclear curvature imposed by an external probe or by cell attachment to either aligned collagen fibers or stiff matrix. Mislocalization is greatly enhanced by lamin A depletion, requires hours for nuclear reentry, and correlates with an increase in pan-nucleoplasmic foci of the DNA damage marker γH2AX. Excess DNA damage is rescued in ruptured nuclei by cooverexpression of multiple DNA repair factors as well as by soft matrix or inhibition of actomyosin tension. Increased contractility has the opposite effect, and stiff tumors with low lamin A indeed exhibit increased nuclear curvature, more frequent nuclear rupture, and excess DNA damage. Additional stresses likely play a role, but the data suggest high curvature promotes nuclear rupture, which compromises retention of DNA repair factors and favors sustained damage.
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DOI：
10.1007/978-1-61779-182-6_6
发表时间：
2011-01-01
期刊：
CELL CYCLE SYNCHRONIZATION: METHODS AND PROTOCOLS
影响因子：
--
作者：
Darzynkiewicz, Zbigniew;Halicka, H. Dorota;Podhorecka, Monika
通讯作者：
Podhorecka, Monika
影响因子：
11.8
作者：
Hernandez, Lidia;Roux, Kyle J.;Stewart, Colin L.
通讯作者：
Stewart, Colin L.
影响因子：
3.5
作者：
De Vos, Winnok H.;Houben, Frederik;Broers, Jos L. V.
通讯作者：
Broers, Jos L. V.
影响因子：
3.8
作者：
Alshareeda, Alaa Tarig;Negm, Ola H.;Rakha, Emad A.
通讯作者：
Rakha, Emad A.
影响因子：
3.7
作者：
Das, Arindam;Grotsky, David A.;Gonzalo, Susana
通讯作者：
Gonzalo, Susana