title: Conserved cysteine residues in the mammalian lamin A tail are essential for cellular responses to ROS generation.
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.
authors.affiliation: School of Biological and Biomedical Sciences, Durham University, Durham, UK.
authors.forename: Vanja
authors.initials: V
authors.lastname: Pekovic
authors.forename: Ian
authors.initials: I
authors.lastname: Gibbs-Seymour
authors.forename: Ewa
authors.initials: E
authors.lastname: Markiewicz
authors.forename: Fahad
authors.initials: F
authors.lastname: Alzoghaibi
authors.forename: Adam M
authors.initials: AM
authors.lastname: Benham
authors.forename: Robert
authors.initials: R
authors.lastname: Edwards
authors.forename: Manfred
authors.initials: M
authors.lastname: Wenhert
authors.forename: Thomas
authors.initials: T
authors.lastname: von Zglinicki
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Hutchison
mesh_terms: D048430:Cell Shape; D016922:Cellular Senescence / Q000235:genetics*; D017124:Conserved Sequence / Q000235:genetics*; D003545:Cysteine / Q000235:genetics / Q000378:metabolism*; D004220:Disulfides / Q000737:chemistry / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000009:adverse effects / Q000494:pharmacology; D007150:Immunohistochemistry; D034904:Lamin Type A / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010957:Plasmids; D061251:Primary Cell Culture; D017434:Protein Structure, Tertiary; D017382:Reactive Oxygen Species / Q000378:metabolism*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014162:Transfection
chemical_list: D004220:Disulfides; D034904:Lamin Type A; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D003545:Cysteine