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

• Published in: The EMBO journal Vol. 28; no. 16; pp. 2414 - 2427
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 19.08.2009; John Wiley & Sons, Ltd; Blackwell Publishing Ltd; Nature Publishing Group
• Subjects: Animals; A‐type lamins; Cell Line; Cell Nucleus - chemistry; Cell Nucleus - metabolism; Chromosomal Proteins, Non-Histone; Deoxyribonucleic acid; DNA; DNA damage; DNA damage response; DNA Repair; DNA-Binding Proteins; EMBO09; EMBO13; Fibroblasts - cytology; Fibroblasts - metabolism; Gene Deletion; Genetics; Genomic Instability; Genomics; Intracellular Signaling Peptides and Proteins - analysis; Intracellular Signaling Peptides and Proteins - metabolism; Lamin Type A - genetics; Lamin Type A - metabolism; Mice; Molecular biology; Mutation; nuclear organization; Proteins; Telomere - chemistry; Telomere - metabolism; telomeres; Tumor Suppressor p53-Binding Protein 1; A‐type lamins; nuclear organization; genomic instability; DNA damage response; telomeres
• ISSN: 0261-4189; 1460-2075
• DOI: 10.1038/emboj.2009.196

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.