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

Lookup NU author(s): Professor Thomas von Zglinicki, Professor Christopher Hutchison

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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.

Publication metadata

Author(s): Pekovic V, Gibbs-Seymour I, Markiewicz E, Alzoghaibi F, Benham AM, Edwards R, Wenhert M, von Zglinicki T, Hutchison CJ

Publication type: Article

Publication status: Published

Journal: Aging Cell

Year: 2011

Volume: 10

Issue: 6

Pages: 1067-1079

Print publication date: 14/11/2011

ISSN (print): 1474-9718

ISSN (electronic): 1474-9726

Publisher: Wiley-Blackwell Publishing Ltd.

URL: http://dx.doi.org/10.1111/j.1474-9726.2011.00750.x

DOI: 10.1111/j.1474-9726.2011.00750.x

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