Open AccessConserved cysteine residues in the mammalian lamin A tail are essential for cellular responses to ROS generation
Author(s) -
Pekovic Vanja,
GibbsSeymour Ian,
Markiewicz Ewa,
Alzoghaibi Fahad,
Benham Adam M.,
Edwards Robert,
Wenhert Manfred,
von Zglinicki Thomas,
Hutchison Christopher J.
Publication year - 2011
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/j.1474-9726.2011.00750.x
Subject(s) - lamin , biology , cysteine , progeria , microbiology and biotechnology , mutant , senescence , oxidative stress , nuclear lamina , conserved sequence , mutation , premature aging , biochemistry , gene , genetics , nuclear protein , peptide sequence , transcription factor , enzyme
Summary Pre‐lamin A and progerin have been implicated in normal aging, and the pathogenesis of age‐related degenerative diseases is termed ‘laminopathies’. Here, we show that mature lamin A has an essential role in cellular fitness and that oxidative damage to lamin A is involved in cellular senescence. Primary human dermal fibroblasts (HDFs) aged replicatively or by pro‐oxidants acquire a range of dysmorphic nuclear shapes. We observed that conserved cysteine residues in the lamin A tail domain become hyperoxidized in senescent fibroblasts, which inhibits the formation of lamin A inter‐ and intramolecular disulfide bonds. Both in the absence of lamin A and in the presence of a lamin A cysteine‐to‐alanine mutant, which eliminates these cysteine residues (522, 588, and 591), mild oxidative stress induced nuclear disorganization and led to premature senescence as a result of decreased tolerance to ROS stimulators. Human dermal fibroblasts lacking lamin A or expressing the lamin A cysteine‐to‐alanine mutant displayed a gene expression profile of ROS‐responsive genes characteristic of chronic ROS stimulation. Our findings suggest that the conserved C‐terminal cysteine residues are essential for lamin A function and that loss or oxidative damage to these cysteine residues promotes cellular senescence.