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dc.contributor.authorCobb, Andrew Men
dc.contributor.authorLarrieu, Delphineen
dc.contributor.authorWarren, Derek Ten
dc.contributor.authorLiu, Yiwenen
dc.contributor.authorSrivastava, Sonalen
dc.contributor.authorSmith, Andrew JOen
dc.contributor.authorBowater, Richard Pen
dc.contributor.authorJackson, Stephenen
dc.contributor.authorShanahan, Catherine Men
dc.date.accessioned2016-08-08T09:15:40Z
dc.date.available2016-08-08T09:15:40Z
dc.date.issued2016-07-27en
dc.identifier.issn1474-9718
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/256986
dc.description.abstractThe 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.
dc.description.sponsorshipBritish Heart Foundation (Grant ID: RG/11/14/29056), Medical Research Council (Grant ID: MR/L019116/1), Cancer Research UK (Grant IDs: C6/A11224, C6946/A14492), European Research Council, European Community Seventh Framework Programme (Grant ID: HEALTH-F2-2010-259893) , Wellcome Trust (Grant ID: WT092096), University of Cambridge
dc.languageEnglishen
dc.language.isoenen
dc.publisherWiley
dc.rightsAttribution 4.0 International*
dc.rightsAttribution 4.0 Internationalen
dc.rightsAttribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subject53BP1en
dc.subjectcytoplasmic–nuclear traffickingen
dc.subjectNUP153en
dc.subjectprelamin Aen
dc.subjectRan gradienten
dc.subjectvascular diseaseen
dc.titlePrelamin A impairs 53BP1 nuclear entry by mislocalizing NUP153 and disrupting the Ran gradienten
dc.typeArticle
dc.description.versionThis is the final version of the article. It first appeared from Wiley via http://dx.doi.org/10.1111/acel.12506en
prism.publicationDate2016en
prism.publicationNameAging Cellen
dc.identifier.doi10.17863/CAM.919
dcterms.dateAccepted2016-06-28en
rioxxterms.versionofrecord10.1111/acel.12506en
rioxxterms.versionVoRen
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/en
rioxxterms.licenseref.startdate2016-07-27en
dc.contributor.orcidLarrieu, Delphine [0000-0002-2335-9361]
dc.contributor.orcidJackson, Stephen [0000-0001-9317-7937]
dc.identifier.eissn1474-9726
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idCancer Research UK (11224)
pubs.funder-project-idMRC (MR/L019116/1)
pubs.funder-project-idCancer Research UK (A18796)
pubs.funder-project-idWellcome Trust (092096/Z/10/Z)
pubs.funder-project-idCancer Research UK (A14492)


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International