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Article: Genomic instability in laminopathy-based premature aging

TitleGenomic instability in laminopathy-based premature aging
Authors
Issue Date2005
PublisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/nm
Citation
Nature Medicine, 2005, v. 11 n. 7, p. 780-785 How to Cite?
AbstractPremature 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.
Persistent Identifierhttp://hdl.handle.net/10722/134121
ISSN
2015 Impact Factor: 30.357
2015 SCImago Journal Rankings: 13.959
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorLiu, Ben_HK
dc.contributor.authorWang, Jen_HK
dc.contributor.authorChan, KMen_HK
dc.contributor.authorTjia, WMen_HK
dc.contributor.authorDeng, Wen_HK
dc.contributor.authorGuan, Xen_HK
dc.contributor.authorHuang, JDen_HK
dc.contributor.authorLi, KMen_HK
dc.contributor.authorChau, PYen_HK
dc.contributor.authorChen, DJen_HK
dc.contributor.authorPei, Den_HK
dc.contributor.authorPendas, AMen_HK
dc.contributor.authorCadiñanos, Jen_HK
dc.contributor.authorLópezOtín, Cen_HK
dc.contributor.authorTse, HFen_HK
dc.contributor.authorHutchison, Cen_HK
dc.contributor.authorChen, Jen_HK
dc.contributor.authorCao, Yen_HK
dc.contributor.authorCheah, KSEen_HK
dc.contributor.authorTryggvason, Ken_HK
dc.contributor.authorZhou, Zen_HK
dc.date.accessioned2011-06-13T07:19:34Z-
dc.date.available2011-06-13T07:19:34Z-
dc.date.issued2005en_HK
dc.identifier.citationNature Medicine, 2005, v. 11 n. 7, p. 780-785en_HK
dc.identifier.issn1078-8956en_HK
dc.identifier.urihttp://hdl.handle.net/10722/134121-
dc.description.abstractPremature 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.en_HK
dc.languageengen_US
dc.publisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/nmen_HK
dc.relation.ispartofNature Medicineen_HK
dc.subject.meshAging, Premature - geneticsen_HK
dc.subject.meshAnimalsen_HK
dc.subject.meshBone Marrow Cells - physiology - radiation effectsen_HK
dc.subject.meshCell Aging - geneticsen_HK
dc.subject.meshChromosomal Proteins, Non-Histoneen_HK
dc.subject.meshChromosome Aberrationsen_HK
dc.subject.meshDNA - geneticsen_HK
dc.subject.meshDNA Damage - geneticsen_HK
dc.subject.meshDNA Repair - physiologyen_HK
dc.subject.meshDNA-Binding Proteins - genetics - metabolismen_HK
dc.subject.meshFibroblasts - pathology - radiation effectsen_HK
dc.subject.meshGamma Raysen_HK
dc.subject.meshGenomic Instabilityen_HK
dc.subject.meshHistones - genetics - metabolism - radiation effectsen_HK
dc.subject.meshHumansen_HK
dc.subject.meshIntracellular Signaling Peptides and Proteins - genetics - metabolismen_HK
dc.subject.meshLamin Type A - genetics - metabolismen_HK
dc.subject.meshMembrane Proteins - genetics - metabolismen_HK
dc.subject.meshMetalloendopeptidases - genetics - metabolismen_HK
dc.subject.meshMiceen_HK
dc.subject.meshMice, Mutant Strainsen_HK
dc.subject.meshNuclear Proteins - genetics - metabolismen_HK
dc.subject.meshPhosphoproteins - genetics - metabolismen_HK
dc.subject.meshProtein Precursors - genetics - metabolismen_HK
dc.subject.meshRad51 Recombinaseen_HK
dc.titleGenomic instability in laminopathy-based premature agingen_HK
dc.typeArticleen_HK
dc.identifier.emailLiu, B: ppliew@hku.hken_HK
dc.identifier.emailChan, KM: ming616@graduate.hku.hken_HK
dc.identifier.emailDeng, W: wdeng@hkucc.hku.hken_HK
dc.identifier.emailGuan, X: xyguan@hkucc.hku.hken_HK
dc.identifier.emailHuang, JD: jdhuang@hkucc.hku.hken_HK
dc.identifier.emailTse, HF: hftse@hkucc.hku.hken_HK
dc.identifier.emailCheah, KSE: hrmbdkc@hku.hken_HK
dc.identifier.emailZhou, Z: zhongjun@hkucc.hku.hken_HK
dc.identifier.authorityLiu, B=rp01485en_HK
dc.identifier.authorityChan, KM=rp01757en_HK
dc.identifier.authorityDeng, W=rp01640en_HK
dc.identifier.authorityGuan, X=rp00454en_HK
dc.identifier.authorityHuang, JD=rp00451en_HK
dc.identifier.authorityTse, HF=rp00428en_HK
dc.identifier.authorityCheah, KSE=rp00342en_HK
dc.identifier.authorityZhou, Z=rp00503en_HK
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1038/nm1266en_HK
dc.identifier.pmid15980864-
dc.identifier.scopuseid_2-s2.0-22544466685en_HK
dc.identifier.hkuros100103-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-22544466685&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume11en_HK
dc.identifier.issue7en_HK
dc.identifier.spage780en_HK
dc.identifier.epage785en_HK
dc.identifier.isiWOS:000230304200035-
dc.publisher.placeUnited Statesen_HK
dc.identifier.f10001026680-
dc.identifier.scopusauthoridLiu, B=7408693394en_HK
dc.identifier.scopusauthoridWang, J=8631854400en_HK
dc.identifier.scopusauthoridChan, KM=8631854500en_HK
dc.identifier.scopusauthoridTjia, WM=8631854600en_HK
dc.identifier.scopusauthoridDeng, W=7202223673en_HK
dc.identifier.scopusauthoridGuan, X=7201463221en_HK
dc.identifier.scopusauthoridHuang, JD=8108660600en_HK
dc.identifier.scopusauthoridLi, KM=7404988734en_HK
dc.identifier.scopusauthoridChau, PY=29267442500en_HK
dc.identifier.scopusauthoridChen, DJ=7405450599en_HK
dc.identifier.scopusauthoridPei, D=7102806599en_HK
dc.identifier.scopusauthoridPendas, AM=35595485200en_HK
dc.identifier.scopusauthoridCadiñanos, J=6506257822en_HK
dc.identifier.scopusauthoridLópezOtín, C=7102600806en_HK
dc.identifier.scopusauthoridTse, HF=7006070805en_HK
dc.identifier.scopusauthoridHutchison, C=7102002532en_HK
dc.identifier.scopusauthoridChen, J=35261693300en_HK
dc.identifier.scopusauthoridCao, Y=7404524342en_HK
dc.identifier.scopusauthoridCheah, KSE=35387746200en_HK
dc.identifier.scopusauthoridTryggvason, K=7102025185en_HK
dc.identifier.scopusauthoridZhou, Z=8631856300en_HK
dc.identifier.citeulike239621-

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