Prelamin A impairs 53BP1 nuclear entry by mislocalizing NUP153 and disrupting the Ran gradient.
Prelamin A impairs 53BP1 nuclear entry by mislocalizing NUP153 and disrupting the Ran gradient.
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DOI：
10.1111/acel.12506
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发表时间：
2016-12
期刊：
影响因子：
7.8
通讯作者：
Shanahan CM
中科院分区：
文献类型：
--
作者：
Cobb AM;Larrieu D;Warren DT;Liu Y;Srivastava S;Smith AJO;Bowater RP;Jackson SP;Shanahan CM
核纤层对于核的正确结构和组织是必不可少的。A型核纤层蛋白的失调会损害基因组稳定性，改变染色质组织并导致过早的血管老化。在这里，我们表明，积累的核纤层蛋白A前体，prelamin A，抑制53BP1招聘的网站的DNA损伤，并增加基础水平的DNA损伤在老年血管平滑肌细胞。我们确定，这种基因组的不稳定性产生通过有缺陷的核进口的53 BP1作为一个结果，异常的拓扑结构排列的核孔蛋白NUP153。我们首次表明，这种核孔蛋白是重要的核本地化的Ran和放松管制的Ran梯度很可能是妥协的核进口的53BP1。重要的是，许多与前核纤层蛋白A表达相关的缺陷在用Remodelin治疗后显著减少，Remodelin是最近报道的逆转与异常核纤层相关的缺陷的小分子。
The nuclear lamina is essential for the proper structure and organization of the nucleus. Deregulation of A‐type lamins can compromise genomic stability, alter chromatin organization and cause premature vascular aging. Here, we show that accumulation of the lamin A precursor, prelamin A, inhibits 53BP1 recruitment to sites of DNA damage and increases basal levels of DNA damage in aged vascular smooth muscle cells. We identify that this genome instability arises through defective nuclear import of 53BP1 as a consequence of abnormal topological arrangement of nucleoporin NUP153. We show for the first time that this nucleoporin is important for the nuclear localization of Ran and that the deregulated Ran gradient is likely to be compromising the nuclear import of 53BP1. Importantly, many of the defects associated with prelamin A expression were significantly reduced upon treatment with Remodelin, a small molecule recently reported to reverse deficiencies associated with abnormal nuclear lamina.
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