Conserved cysteine residues in the mammalian lamin A tail are essential for cellular responses to ROS generation

Pekovic, V.; Gibbs-Seymour, I.D.; Markiewicz, E.; Alzoghaibi, F.; Benham, A.M.; Edwards, R.; Wehnert, M.; von Zlignicki, T.; Hutchison, C.J.

Abstract

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.

Citation

Pekovic, V., Gibbs-Seymour, I., Markiewicz, E., Alzoghaibi, F., Benham, A., Edwards, R., …Hutchison, C. (2011). Conserved cysteine residues in the mammalian lamin A tail are essential for cellular responses to ROS generation. Aging Cell, 10(6), 1067-1079. https://doi.org/10.1111/j.1474-9726.2011.00750.x

• Journal Article Type: Article
• Acceptance Date: Sep 16, 2011
• Publication Date: Dec 1, 2011
• Deposit Date: Mar 30, 2012
• Journal: Aging Cell
• Print ISSN: 1474-9718
• Electronic ISSN: 1474-9726
• Publisher: Anatomical Society of Great Britain and Ireland
• Peer Reviewed: Peer Reviewed
• Volume: 10
• Issue: 6
• Pages: 1067-1079
• DOI: https://doi.org/10.1111/j.1474-9726.2011.00750.x
• Keywords: Lamin A, Aging, Senescence, Oxidative stress, Redox homeostasis, Laminopathies.
• Public URL: https://durham-repository.worktribe.com/output/1478840