Novel roles for A-type lamins in telomere biology and the DNA damage response pathway
Novel roles for A-type lamins in telomere biology and the DNA damage response pathway
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DOI：
10.1038/emboj.2009.196
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发表时间：
2009-08-19
期刊：
影响因子：
11.4
通讯作者：
Gonzalo, Susana
中科院分区：
文献类型：
--
作者：
Gonzalez-Suarez, Ignacio;Redwood, Abena B.;Gonzalo, Susana
A型核纤层蛋白是中间丝蛋白，为调节核结构和功能的蛋白质复合物提供支架。LMNA基因的突变与多种称为核纤层蛋白病的退行性疾病有关，而核纤层蛋白表达的变化与肿瘤发生有关。受A型核纤层蛋白改变影响的分子途径以及它们如何导致疾病还知之甚少。在这里，我们表明，A型核纤层蛋白在维持端粒结构，长度和功能，并在稳定的53 BP 1，DNA损伤反应（DDR）途径的组成部分有一个关键的作用。A型核纤层蛋白的缺失改变了端粒的核分布，并导致端粒缩短、端粒异染色质缺陷和基因组不稳定性增加。此外，A型核纤层蛋白对于通过非同源末端连接、通过53 BP 1的稳定化而纯化的功能失调的端粒的加工是必需的。这项研究显示了A型核纤层蛋白在维持基因组完整性方面的新功能，并表明端粒生物学的改变和DDR的缺陷有助于核纤层蛋白相关疾病的发病机制。The EMBO Journal（2009）28，2414-2427. doi：10.1038/doj.2009.196; 2009年7月23日在线发布
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