Gonzalez-Suarez Ignacio, Redwood Abena B, Perkins Stephanie M, Vermolen Bart, Lichtensztejin Daniel, Grotsky David A, Morgado-Palacin Lucia, Gapud Eric J, Sleckman Barry P, Sullivan Teresa, Sage Julien, Stewart Colin L, Mai Sabine, Gonzalo Susana
Department of Radiation Oncology, Washington University School of Medicine, St Louis, MO 63108, USA.
EMBO J. 2009 Aug 19;28(16):2414-27. doi: 10.1038/emboj.2009.196. Epub 2009 Jul 23.
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.
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基因的突变与多种被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相关。目前对受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了解甚少。在这里，我们表明A型核纤层蛋白在维持端粒结构、长度和功能以及稳定DNA损伤反应（DDR）途径的组成部分53BP1方面具有关键作用。A型核纤层蛋白的缺失会改变端粒的核分布，导致端粒缩短、端粒异染色质缺陷以及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处理功能失调的端粒是必需的，推测是通过稳定53BP1来实现的。这项研究揭示了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缺陷促成了核纤层蛋白相关疾病的发病机制。
