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

Ignacio Gonzalez-Suarez, Abena B. Redwood, Stephanie M. Perkins, Bart Vermolen, Daniel Lichtensztejin, David A. Grotsky, Lucia Morgado-Palacin, Eric J. Gapud, Barry P. Sleckman, Teresa Sullivan, Julien Sage, Colin L. Stewart, Sabine Mai, Susana Gonzalo

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)2414-2427
Number of pages14
JournalEMBO Journal
Volume28
Issue number16
DOIs
StatePublished - Aug 19 2009
Externally publishedYes

Keywords

  • A-type lamins
  • DNA damage response
  • Genomic instability
  • Nuclear organization
  • Telomeres

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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