Cobb Andrew M, Larrieu Delphine, Warren Derek T, Liu Yiwen, Srivastava Sonal, Smith Andrew J O, Bowater Richard P, Jackson Stephen P, Shanahan Catherine M
The James Black Centre, King's College London, 125 Coldharbour Lane, London, SE5 9NU, UK.
Wellcome Trust/Cancer Research UK Gurdon Institute, The Henry Wellcome Building of Cancer and Developmental Biology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QN, UK.
Aging Cell. 2016 Dec;15(6):1039-1050. doi: 10.1111/acel.12506. Epub 2016 Jul 27.
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.
核纤层对于细胞核的正常结构和组织至关重要。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血管过早衰老。在此，我们表明核纤层蛋白A前体（前核纤层蛋白A）的积累会抑制53BP1募集到DNA损伤位点，并增加衰老血管平滑肌细胞中的基础DNA损伤水平。我们确定这种基因组不稳定性是由于核孔蛋白NUP153的异常拓扑排列导致53BP1的核输入缺陷而产生的。我们首次表明这种核孔蛋白对Ran的核定位很重要，并且失调的Ran梯度可能会损害53BP1的核输入。重要的是，在用Remodelin处理后，许多与前核纤层蛋白A表达相关的缺陷显著减少，Remodelin是一种最近报道可逆转与异常核纤层相关缺陷的小分子。
