Prelamin A impairs 53BP1 nuclear entry by mislocalizing NUP153 and disrupting the Ran gradient |
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| Authors: | Andrew M Cobb Delphine Larrieu Derek T Warren Yiwen Liu Sonal Srivastava Andrew J O Smith Richard P Bowater Stephen P Jackson Catherine M Shanahan |
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| Institution: | 1. The James Black Centre, King's College London, London, UK;2. Wellcome Trust/Cancer Research UK Gurdon Institute, The Henry Wellcome Building of Cancer and Developmental Biology, University of Cambridge, Cambridge, UK;3. School of Biological Sciences, University of East Anglia, Norwich, UK |
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| Abstract: | 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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| Keywords: | 53BP1 cytoplasmic– nuclear trafficking NUP153 prelamin A Ran gradient vascular disease |
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