Novel roles for A-type lamins in telomere biology and the DNA damage response pathway.

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【作者】 Ignacio González-Suárez  Abena B. Redwood  Stephanie Perkins  Bart J. Vermolen  Daniel Lichtensztejin  David A. Grotsky  Lucia Morgado-Palacin  Eric J. Gapud  Barry P Sleckman  Teresa L. Sullivan  Julien Sage  Colin Lawson Stewart  Sabine Mai  S Gonzalo 

【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.

【刊名】The EMBO journal

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