title: Novel roles for A-type lamins in telomere biology and the DNA damage response pathway.
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.
authors.affiliation: Department of Radiation Oncology, Washington University School of Medicine, St Louis, MO 63108, USA.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Gonzalez-Suarez
authors.forename: Abena B
authors.initials: AB
authors.lastname: Redwood
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Perkins
authors.forename: Bart
authors.initials: B
authors.lastname: Vermolen
authors.forename: Daniel
authors.initials: D
authors.lastname: Lichtensztejin
authors.forename: David A
authors.initials: DA
authors.lastname: Grotsky
authors.forename: Lucia
authors.initials: L
authors.lastname: Morgado-Palacin
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Gapud
authors.forename: Barry P
authors.initials: BP
authors.lastname: Sleckman
authors.forename: Teresa
authors.initials: T
authors.lastname: Sullivan
authors.forename: Julien
authors.initials: J
authors.lastname: Sage
authors.forename: Colin L
authors.initials: CL
authors.lastname: Stewart
authors.forename: Sabine
authors.initials: S
authors.lastname: Mai
authors.forename: Susana
authors.initials: S
authors.lastname: Gonzalo
mesh_terms: D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000737:chemistry / Q000378:metabolism; D002868:Chromosomal Proteins, Non-Histone; D004260:DNA Repair; D004268:DNA-Binding Proteins; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D017353:Gene Deletion; D042822:Genomic Instability; D047908:Intracellular Signaling Peptides and Proteins / Q000032:analysis / Q000378:metabolism; D034904:Lamin Type A / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D016615:Telomere / Q000737:chemistry / Q000378:metabolism*; D000071857:Tumor Suppressor p53-Binding Protein 1
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D034904:Lamin Type A; C498302:Trp53bp1 protein, mouse; D000071857:Tumor Suppressor p53-Binding Protein 1