Nuclear constriction segregates mobile nuclear proteins away from chromatin.
Nuclear constriction segregates mobile nuclear proteins away from chromatin.
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DOI：
10.1091/mbc.e16-06-0428
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发表时间：
2016-12-15
影响因子：
3.3
通讯作者：
Discher DE
中科院分区：
文献类型：
--
作者：
Irianto J;Pfeifer CR;Bennett RR;Xia Y;Ivanovska IL;Liu AJ;Greenberg RA;Discher DE
细胞核扭曲，如在3D迁移中，局部集中染色质，并导致细胞核内移动的因子的互补分离。这是不可避免的，因为染色质是可压缩的。当细胞挤压其细胞核穿过邻近组织、穿透基底膜或进入小毛细血管时，染色质密度和核因子原则上可以被物理扰动。在此，在癌细胞通过刚性微孔迁移和被动拉入微量移液管中时，观察到染色质的局部压实与移动的因子的耗尽一致。先前通过分子迁移率测量估计异染色质/常染色质占据大约三分之二核体积的体积分数f，但是基于被拉入狭窄收缩的几个癌细胞系中DNA和组蛋白的相对强度，f可以容易地局部增加到接近100%。相比之下，细胞核中的移动的蛋白，包括十几种起DNA修复蛋白作用的蛋白（例如，BRCA 1、53 BP 1）或核酸酶（例如，Cas9，FokI）在收缩部内耗尽，接近0%。这种损失，加上偶尔的核膜破裂，可能会产生重要的功能后果。针对1号染色体上一个位点的核酸酶的研究确实表明，收缩的迁移延迟了DNA损伤。
Nuclear distortion such as in 3D migration concentrates chromatin locally and causes complementary segregation of mobile factors within the nucleus. This is unavoidable because chromatin is compressible. As a cell squeezes its nucleus through adjacent tissue, penetrates a basement membrane, or enters a small blood capillary, chromatin density and nuclear factors could in principle be physically perturbed. Here, in cancer cell migration through rigid micropores and in passive pulling into micropipettes, local compaction of chromatin is observed coincident with depletion of mobile factors. Heterochromatin/euchromatin was previously estimated from molecular mobility measurements to occupy a volume fraction f of roughly two-thirds of the nuclear volume, but based on the relative intensity of DNA and histones in several cancer cell lines drawn into narrow constrictions, f can easily increase locally to nearly 100%. By contrast, mobile proteins in the nucleus, including a dozen that function as DNA repair proteins (e.g., BRCA1, 53BP1) or nucleases (e.g., Cas9, FokI), are depleted within the constriction, approaching 0%. Such losses—compounded by the occasional rupture of the nuclear envelope—can have important functional consequences. Studies of a nuclease that targets a locus in chromosome-1 indeed show that constricted migration delays DNA damage.