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

EMBO J. 2009 Aug 19;28(16):2414-27. doi: 10.1038/emboj.2009.196. Epub 2009 Jul 23.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cell Nucleus / chemistry
  • Cell Nucleus / metabolism
  • Chromosomal Proteins, Non-Histone
  • DNA Repair*
  • DNA-Binding Proteins
  • Fibroblasts / cytology
  • Fibroblasts / metabolism
  • Gene Deletion
  • Genomic Instability
  • Intracellular Signaling Peptides and Proteins / analysis
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Lamin Type A / genetics*
  • Lamin Type A / metabolism*
  • Mice
  • Telomere / chemistry
  • Telomere / metabolism*
  • Tumor Suppressor p53-Binding Protein 1

Substances

  • Chromosomal Proteins, Non-Histone
  • DNA-Binding Proteins
  • Intracellular Signaling Peptides and Proteins
  • Lamin Type A
  • Trp53bp1 protein, mouse
  • Tumor Suppressor p53-Binding Protein 1