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Prelamin A impairs 53BP1 nuclear entry by mislocalizing NUP153 and disrupting the Ran gradient.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Cobb, Andrew M 
Warren, Derek T 
Liu, Yiwen 
Srivastava, Sonal 

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.

Description

Keywords

53BP1, NUP153, Ran gradient, cytoplasmic-nuclear trafficking, prelamin A, vascular disease

Journal Title

Aging Cell

Conference Name

Journal ISSN

1474-9718
1474-9726

Volume Title

Publisher

Wiley
Sponsorship
Cancer Research Uk (None)
Medical Research Council (MR/L019116/1)
Cancer Research UK (18796)
Wellcome Trust (092096/Z/10/Z)
Cancer Research Uk (None)
British 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