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Novel roles for A-type lamins in telomere biology and the DNA damage response pathway
被引:184
作者:
Gonzalez-Suarez, Ignacio
[2
]
Redwood, Abena B.
[2
]
Perkins, Stephanie M.
[2
]
Vermolen, Bart
[3
]
Lichtensztejin, Daniel
[4
]
Grotsky, David A.
[2
]
Morgado-Palacin, Lucia
[2
]
Gapud, Eric J.
[5
]
Sleckman, Barry P.
[5
]
Sullivan, Teresa
[6
]
Sage, Julien
[7
,8
]
Stewart, Colin L.
[6
,9
]
Mai, Sabine
[4
]
Gonzalo, Susana
[1
,2
]
机构:
[1] Washington Univ, Sch Med, Dept Radiat Oncol, Radiat & Canc Biol Div, St Louis, MO 63108 USA
[2] Washington Univ, Sch Med, Dept Cell Biol & Physiol, St Louis, MO 63108 USA
[3] Univ Twente, Fac Sci & Technol, Biophys Engn Grp, Enschede, Netherlands
[4] Univ Manitoba, Manitoba Inst Cell Biol, Winnipeg, MB, Canada
[5] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63108 USA
[6] NCI, Canc & Dev Biol Lab, Frederick, MD 21701 USA
[7] Stanford Univ, Dept Pediat, Stanford, CA 94305 USA
[8] Stanford Univ, Dept Genet, Stanford, CA 94305 USA
[9] Inst Med Biol, Singapore, Singapore
关键词:
A-type lamins;
DNA damage response;
genomic instability;
nuclear organization;
telomeres;
REPEAT-CONTAINING RNA;
STRAND BREAK REPAIR;
NUCLEAR LAMINS;
3-DIMENSIONAL ORGANIZATION;
HEMATOLOGIC MALIGNANCIES;
RETINOBLASTOMA PROTEIN;
EPIGENETIC REGULATION;
MAMMALIAN TELOMERES;
C CONTAINS;
RB FAMILY;
D O I:
10.1038/emboj.2009.196
中图分类号:
Q5 [生物化学];
Q7 [分子生物学];
学科分类号:
071010 ;
081704 ;
摘要:
A-type lamins are intermediate filament proteins that provide a scaffold for protein complexes regulating nuclear structure and function. Mutations in the LMNA gene are linked to a variety of degenerative disorders termed laminopathies, whereas changes in the expression of lamins are associated with tumourigenesis. The molecular pathways affected by alterations of A-type lamins and how they contribute to disease are poorly understood. Here, we show that A-type lamins have a key role in the maintenance of telomere structure, length and function, and in the stabilization of 53BP1, a component of the DNA damage response (DDR) pathway. Loss of A-type lamins alters the nuclear distribution of telomeres and results in telomere shortening, defects in telomeric heterochromatin, and increased genomic instability. In addition, A-type lamins are necessary for the processing of dysfunctional telomeres by non-homologous end joining, putatively through stabilization of 53BP1. This study shows new functions for A-type lamins in the maintenance of genomic integrity, and suggests that alterations of telomere biology and defects in DDR contribute to the pathogenesis of lamin-related diseases. The EMBO Journal (2009) 28, 2414-2427. doi:10.1038/emboj.2009.196; Published online 23 July 2009
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页码:2414 / 2427
页数:14
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