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Durham University

Department of Biosciences

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Publication details for Dr Adam Benham

Pekovic, V., Gibbs-Seymour, I.D., Markiewicz, E., Alzoghaibi, F., Benham, A.M., Edwards, R., Wehnert, M., von Zlignicki, T. & Hutchison, C.J. (2011). Conserved cysteine residues in the mammalian lamin A tail are essential for cellular responses to ROS generation. Aging Cell 10(6): 1067-1079.

Author(s) from Durham

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.