Genomic instability in laminopathy-based premature aging.
Premature aging syndromes often result from mutations in nuclear proteins involved in the maintenance of genomic integrity. Lamin A is a major component of the nuclear lamina and nuclear skeleton. Truncation in lamin A causes Hutchinson-Gilford progerial syndrome (HGPS), a severe form of early-onset premature aging. Lack of functional Zmpste24, a metalloproteinase responsible for the maturation of prelamin A, also results in progeroid phenotypes in mice and humans. We found that Zmpste24-deficient mouse embryonic fibroblasts (MEFs) show increased DNA damage and chromosome aberrations and are more sensitive to DNA-damaging agents. Bone marrow cells isolated from Zmpste24-/- mice show increased aneuploidy and the mice are more sensitive to DNA-damaging agents. Recruitment of p53 binding protein 1 (53BP1) and Rad51 to sites of DNA lesion is impaired in Zmpste24-/- MEFs and in HGPS fibroblasts, resulting in delayed checkpoint response and defective DNA repair. Wild-type MEFs ectopically expressing unprocessible prelamin A show similar defects in checkpoint response and DNA repair. Our results indicate that unprocessed prelamin A and truncated lamin A act dominant negatively to perturb DNA damage response and repair, resulting in genomic instability which might contribute to laminopathy-based premature aging.
Department of Biochemistry, University of Hong Kong, 21 Sassoon Road, Hong Kong.
Baohua
B
Liu
Jianming
J
Wang
Kui Ming
KM
Chan
Wai Mui
WM
Tjia
Wen
W
Deng
Xinyuan
X
Guan
Jian-dong
JD
Huang
Kai Man
KM
Li
Pui Yin
PY
Chau
David J
DJ
Chen
Duanqing
D
Pei
Alberto M
AM
Pendas
Juan
J
Cadiñanos
Carlos
C
López-Otín
Hung Fat
HF
Tse
Chris
C
Hutchison
Junjie
J
Chen
Yihai
Y
Cao
Kathryn S E
KS
Cheah
Karl
K
Tryggvason
Zhongjun
Z
Zhou
D019588:Aging, Premature / Q000235:genetics*; D000818:Animals; D001854:Bone Marrow Cells / Q000502:physiology / Q000528:radiation effects; D016922:Cellular Senescence / Q000235:genetics; D002868:Chromosomal Proteins, Non-Histone; D002869:Chromosome Aberrations; D004247:DNA / Q000235:genetics; D004249:DNA Damage / Q000235:genetics*; D004260:DNA Repair / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000473:pathology / Q000528:radiation effects; D005720:Gamma Rays; D042822:Genomic Instability; D006657:Histones / Q000235:genetics / Q000378:metabolism / Q000528:radiation effects; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D034904:Lamin Type A / Q000235:genetics* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008666:Metalloendopeptidases / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D051135:Rad51 Recombinase; D000071857:Tumor Suppressor p53-Binding Protein 1
D002868:Chromosomal Proteins, Non-Histone; D004247:DNA; D004268:DNA-Binding Proteins; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; D034904:Lamin Type A; D008565:Membrane Proteins; D008666:Metalloendopeptidases; D009687:Nuclear Proteins; D010750:Phosphoproteins; D011498:Protein Precursors; D051135:Rad51 Recombinase; D000071857:Tumor Suppressor p53-Binding Protein 1; C498301:TP53BP1 protein, human; C498302:Trp53bp1 protein, mouse; C090764:prelamin A; C495153:RAD51 protein, human; C495154:Rad51 protein, mouse; C491250:Zmpste24 protein, mouse; C475961:gamma-H2AX protein, mouse