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

Robert Edwards; Pekovic,V.; Gibbs-Seymour, I.; Markiewicz, E.; Alzoghaibi, F.; Benham, A.M; Wenhert, M.; von Zglinicki, T.; Hutchison, C.J

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

Robert Edwards, Pekovic,V., Gibbs-Seymour, I., Markiewicz, E., Alzoghaibi, F., Benham, A.M, Wenhert, M., von Zglinicki, T., Hutchison, C.J

CNAP

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	1067-1079
Journal	Aging Cell
Volume	10
Publication status	Published - 2011

Cite this

@article{29b99796e78244dabbfaf61940cddb49,

title = "Conserved cysteine residues in the mammalian lamin A tail are essential for cellular resposes 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 {\textquoteleft}laminopathies{\textquoteright}. 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.",

author = "Robert Edwards and Pekovic,V. and {Gibbs-Seymour, I.} and {Markiewicz, E.} and {Alzoghaibi, F.} and {Benham, A.M} and {Wenhert, M.} and {von Zglinicki, T.} and {Hutchison, C.J}",

year = "2011",

language = "English",

volume = "10",

pages = "1067--1079",

journal = "Aging Cell",

}

TY - JOUR

T1 - Conserved cysteine residues in the mammalian lamin A tail are essential for cellular resposes to ROS generation.

AU - Edwards, Robert

AU - Pekovic,V.

AU - Gibbs-Seymour, I.

AU - Markiewicz, E.

AU - Alzoghaibi, F.

AU - Benham, A.M

AU - Wenhert, M.

AU - von Zglinicki, T.

AU - Hutchison, C.J

PY - 2011

Y1 - 2011

N2 - 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.

AB - 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.

M3 - Article

VL - 10

SP - 1067

EP - 1079

JO - Aging Cell

JF - Aging Cell

ER -