Open AccessPrelamin A impairs 53 BP 1 nuclear entry by mislocalizing NUP 153 and disrupting the Ran gradient
Author(s) -
Cobb Andrew M.,
Larrieu Delphine,
Warren Derek T.,
Liu Yiwen,
Srivastava Sonal,
Smith Andrew J. O.,
Bowater Richard P.,
Jackson Stephen P.,
Shanahan Catherine M.
Publication year - 2016
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.12506
Subject(s) - nuclear lamina , lamin , nucleoporin , biology , ran , nuclear transport , chromatin , microbiology and biotechnology , nuclear pore , nuclear protein , genome instability , inner membrane , nuclear localization sequence , cell nucleus , dna damage , genetics , nucleus , dna , gene , mitochondrion , transcription factor
Summary 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 53 BP 1 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 53 BP 1 as a consequence of abnormal topological arrangement of nucleoporin NUP 153. 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 53 BP 1. 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.