ABSTRACT Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disorder caused by a mutation of lamin A, which contributes to nuclear architecture and the spatial organization of chromatin in the nucleus. The expression of a lamin A mutant, named progerin, leads to functional and structural disruption of nuclear organization. Since progerin lacks a part of the actin-binding site of lamin A, we hypothesized that nuclear actin dynamics and function are altered in HGPS cells. Nuclear F-actin is required for the organization of nuclear shape, transcriptional regulation, DNA damage repair, and activation of Wnt/β-catenin signaling. Here we show that the expression of progerin decreases nuclear F-actin and impairs F-actin-regulated transcription. When nuclear F-actin levels are increased by overexpression of nuclear-targeted actin or by using jasplakinolide, a compound that stabilizes F-actin, the irregularity of nuclear shape and defects in gene expression can be reversed. These observations provide evidence for a novel relationship between nuclear actin and the etiology of HGPS.

中文翻译：

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Hutchinson-Gilford早衰综合征中核F-肌动蛋白形成的损害及其与细胞表型的相关性

摘要 Hutchinson-Gilford 早衰综合征 (HGPS) 是由 lamin A 突变引起的过早衰老障碍，它有助于核结构和细胞核中染色质的空间组织。一种名为 progerin 的 lamin A 突变体的表达导致核组织的功能和结构破坏。由于 progerin 缺乏 lamin A 的肌动蛋白结合位点的一部分，我们假设核肌动蛋白动力学和功能在 HGPS 细胞中发生了改变。核形状的组织、转录调控、DNA 损伤修复和 Wnt/β-连环蛋白信号传导的激活都需要核 F-肌动蛋白。在这里我们显示 progerin 的表达降低核 F-肌动蛋白并损害 F-肌动蛋白调节的转录。当核靶向肌动蛋白的过度表达或使用 jasplakinolide（一种稳定 F-肌动蛋白的化合物）增加核 F-肌动蛋白水平时，可以逆转核形状的不规则性和基因表达的缺陷。这些观察结果为核肌动蛋白与 HGPS 病因之间的新关系提供了证据。