title: Prelamin A impairs 53BP1 nuclear entry by mislocalizing NUP153 and disrupting the Ran gradient.
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.
authors.affiliation: The James Black Centre, King's College London, 125 Coldharbour Lane, London, SE5 9NU, UK.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Cobb
authors.affiliation: 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.
authors.forename: Delphine
authors.identifier: http://orcid.org/0000-0002-2335-9361
authors.initials: D
authors.lastname: Larrieu
authors.affiliation: The James Black Centre, King's College London, 125 Coldharbour Lane, London, SE5 9NU, UK.
authors.forename: Derek T
authors.initials: DT
authors.lastname: Warren
authors.affiliation: The James Black Centre, King's College London, 125 Coldharbour Lane, London, SE5 9NU, UK.
authors.forename: Yiwen
authors.initials: Y
authors.lastname: Liu
authors.affiliation: The James Black Centre, King's College London, 125 Coldharbour Lane, London, SE5 9NU, UK.
authors.forename: Sonal
authors.initials: S
authors.lastname: Srivastava
authors.affiliation: School of Biological Sciences, University of East Anglia, Norwich, NR4 7TJ, UK.
authors.forename: Andrew J O
authors.initials: AJO
authors.lastname: Smith
authors.affiliation: School of Biological Sciences, University of East Anglia, Norwich, NR4 7TJ, UK.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Bowater
authors.affiliation: 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.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Jackson
authors.affiliation: The James Black Centre, King's College London, 125 Coldharbour Lane, London, SE5 9NU, UK.
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Shanahan
keywords: 53BP1; NUP153; Ran gradient; cytoplasmic-nuclear trafficking; prelamin A; vascular disease