Novel roles for A-type lamins in telomere biology and the DNA damage response pathway.
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.
Gonzalez-Suarez
Ignacio
I
Department of Radiation Oncology, Washington University School of Medicine, St Louis, MO 63108, USA.
Redwood
Abena B
AB
Perkins
Stephanie M
SM
Vermolen
Bart
B
Lichtensztejin
Daniel
D
Grotsky
David A
DA
Morgado-Palacin
Lucia
L
Gapud
Eric J
EJ
Sleckman
Barry P
BP
Sullivan
Teresa
T
Sage
Julien
J
Stewart
Colin L
CL
Mai
Sabine
S
Gonzalo
Susana
S
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
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