Increased plasticity of the nuclear envelope and hypermobility of telomeres due to the loss of A-type lamins
Increased plasticity of the nuclear envelope and hypermobility of telomeres due to the loss of A-type lamins
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DOI：
10.1016/j.bbagen.2010.01.002
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发表时间：
2010-04-01
影响因子：
3
通讯作者：
Van Oostveldt, Patrick
中科院分区：
文献类型：
--
作者：
De Vos, Winnok H.;Houben, Frederik;Van Oostveldt, Patrick
背景：核板层为细胞核提供结构支持，并在确定细胞核结构中起核心作用。其丝状组分核纤层蛋白的缺陷导致一类统称为核纤层蛋白病的疾病。在细胞水平上，核纤层蛋白突变影响细胞核的物理完整性和核-细胞骨架相互作用，导致对机械应力的敏感性增加和基因表达改变。在这项研究中，我们定量比较了来自纯合无义LMNA突变患者和Hutchinson-Gilford早衰综合征患者的成纤维细胞与野生型真皮成纤维细胞的核变形和染色质迁移率，基于mCitrine标记的端粒结合蛋白TRF 2的可视化与光经济成像技术和cytometric analysis.Results：没有施加外力，我们发现，功能核纤层蛋白A/C的情况下，导致增加核可塑性的小时和分钟的时间尺度，但也增加核内流动性下降到第二个时间尺度。相比之下，早老症细胞显示出整体降低的核动力学。实验操作（法尼基转移酶抑制或核纤层蛋白A/C沉默）证实，这些变化的流动性是由异常或减少核纤层蛋白A/C expression.Conclusions：这些观察表明，A型核纤层蛋白影响核膜和端粒dynamics.General意义：由于核功能的动力学的关键作用，这些差异可能有助于或代表核纤层蛋白病发展的新机制。(c)2010爱思唯尔有限公司版权所有。
Background: The nuclear lamina provides structural support to the nucleus and has a central role in defining nuclear organization. Defects in its filamentous constituents, the lamins, lead to a class of diseases collectively referred to as laminopathies. On the cellular level, lamin mutations affect the physical integrity of nuclei and nucleo-cytoskeletal interactions, resulting in increased susceptibility to mechanical stress and altered gene expression.Methods: In this study we quantitatively compared nuclear deformation and chromatin mobility in fibroblasts from a homozygous nonsense LMNA mutation patient and a Hutchinson-Gilford progeria syndrome patient with wild type dermal fibroblasts, based on the visualization of mCitrine labeled telomere-binding protein TRF2 with light-economical imaging techniques and cytometric analyses.Results: Without application of external forces, we found that the absence of functional lamin A/C leads to increased nuclear plasticity on the hour and minute time scale but also to increased intranuclear mobility down to the second time scale. In contrast, progeria cells show overall reduced nuclear dynamics. Experimental manipulation (farnesyltransferase inhibition or lamin A/C silencing) confirmed that these changes in mobility are caused by abnormal or reduced lamin A/C expression.Conclusions: These observations demonstrate that A-type lamins affect both nuclear membrane and telomere dynamics.General significance: Because of the pivotal role of dynamics in nuclear function, these differences likely Contribute to or represent novel mechanisms in laminopathy development. (c) 2010 Elsevier B.V. All rights reserved.