Prelamin A impairs 53BP1 nuclear entry by mislocalizing NUP153 and disrupting the Ran gradient.
| Title: | Prelamin A impairs 53BP1 nuclear entry by mislocalizing NUP153 and disrupting the Ran gradient. |
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| Authors: | Cobb AM; The James Black Centre, King's College London, 125 Coldharbour Lane, London, SE5 9NU, UK.; Larrieu D; 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.; Warren DT; The James Black Centre, King's College London, 125 Coldharbour Lane, London, SE5 9NU, UK.; Liu Y; The James Black Centre, King's College London, 125 Coldharbour Lane, London, SE5 9NU, UK.; Srivastava S; The James Black Centre, King's College London, 125 Coldharbour Lane, London, SE5 9NU, UK.; Smith AJO; School of Biological Sciences, University of East Anglia, Norwich, NR4 7TJ, UK.; Bowater RP; School of Biological Sciences, University of East Anglia, Norwich, NR4 7TJ, UK.; Jackson SP; 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.; Shanahan CM; The James Black Centre, King's College London, 125 Coldharbour Lane, London, SE5 9NU, UK. |
| Source: | Aging cell [Aging Cell] 2016 Dec; Vol. 15 (6), pp. 1039-1050. Date of Electronic Publication: 2016 Jul 27. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Wiley-Blackwell Country of Publication: England NLM ID: 101130839 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1474-9726 (Electronic) Linking ISSN: 14749718 NLM ISO Abbreviation: Aging Cell Subsets: PubMed not MEDLINE |
| Imprint Name(s): | Publication: Oxford, UK : Wiley-Blackwell; Original Publication: Oxford, UK : Blackwell Pub., c2002- |
| 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.; (© 2016 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.) |
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| Grant Information: | WT092096 United Kingdom WT_ Wellcome Trust; International ERC_ European Research Council; 18796 United Kingdom CRUK_ Cancer Research UK; RG/11/14/29056 United Kingdom BHF_ British Heart Foundation; United Kingdom WT_ Wellcome Trust; MR/L019116/1 United Kingdom MRC_ Medical Research Council; 11224 United Kingdom CRUK_ Cancer Research UK |
| Contributed Indexing: | Keywords: 53BP1; NUP153; Ran gradient; cytoplasmic-nuclear trafficking; prelamin A; vascular disease |
| Entry Date(s): | Date Created: 20160729 Latest Revision: 20250530 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC5114580 |
| DOI: | 10.1111/acel.12506 |
| PMID: | 27464478 |
| Database: | MEDLINE |
Journal Article