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
引用
收藏
页码:2414 / 2427
页数:14
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