title: Lamin A Δexon9 mutation leads to telomere and chromatin defects but not genomic instability.
abstract: Over 300 mutations in the LMNA gene, encoding A-type lamins, are associated with 15 human degenerative disorders and premature aging syndromes. Although genomic instability seems to contribute to the pathophysiology of some laminopathies, there is limited information about what mutations cause genomic instability and by which molecular mechanisms. Mouse embryonic fibroblasts depleted of A-type lamins or expressing mutants lacking exons 8-11 (Lmna(Δ8-11/Δ8-11)) exhibit alterations in telomere biology and DNA repair caused by cathepsin L-mediated degradation of 53BP1 and reduced expression of BRCA1 and RAD51. Thus, a region encompassing exons 8-11 seems essential for genome integrity. Given that deletion of lamin A exon 9 in the mouse (Lmna(Δ9/Δ9)) results in a progeria phenotype, we tested if this domain is important for genome integrity. Lmna(Δ9/Δ9) MEFs exhibit telomere shortening and heterochromatin alterations but do not activate cathepsin L-mediated degradation of 53BP1 and maintain expression of BRCA1 and RAD51. Accordingly, Lmna(Δ9/Δ9) MEFs do not present genomic instability, and expression of mutant lamin A Δexon9 in lamin-depleted cells restores DNA repair factors levels and partially rescues nuclear abnormalities. These data reveal that the domain encoded by exon 9 is important to maintain telomere homeostasis and heterochromatin structure but does not play a role in DNA repair, thus pointing to other exons in the lamin A tail as responsible for the genomic instability phenotype in Lmna(Δ8-11/Δ8-11) mice. Our study also suggests that the levels of DNA repair factors 53BP1, BRCA1 and RAD51 could potentially serve as biomarkers to identify laminopathies that present with genomic instability.
authors.affiliation: Edward A Doisy Department of Biochemistry and Molecular Biology; School of Medicine; St Louis University; St Louis, MO USA; Departments of Radiation Oncology and Cell Biology & Physiology; School of Medicine; Washington University; St Louis, MO USA; Buck Institute for Research on Aging; Novato, CA USA; Institute of Medical Biology; Biopolis; Singapore.
authors.forename: Arindam
authors.initials: A
authors.lastname: Das
authors.forename: David A
authors.initials: DA
authors.lastname: Grotsky
authors.forename: Martin A
authors.initials: MA
authors.lastname: Neumann
authors.forename: Ray
authors.initials: R
authors.lastname: Kreienkamp
authors.forename: Ignacio
authors.initials: I
authors.lastname: Gonzalez-Suarez
authors.forename: Abena B
authors.initials: AB
authors.lastname: Redwood
authors.forename: Brian K
authors.initials: BK
authors.lastname: Kennedy
authors.forename: Colin L
authors.initials: CL
authors.lastname: Stewart
authors.forename: Susana
authors.initials: S
authors.lastname: Gonzalo
mesh_terms: D000818:Animals; D019313:BRCA1 Protein / Q000378:metabolism; D002460:Cell Line; D002843:Chromatin / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D004260:DNA Repair / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism; D005091:Exons / Q000235:genetics*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D042822:Genomic Instability / Q000235:genetics*; D006570:Heterochromatin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D034904:Lamin Type A / Q000235:genetics*; D051379:Mice; D051135:Rad51 Recombinase / Q000378:metabolism; D017384:Sequence Deletion / Q000235:genetics*; D016615:Telomere / Q000235:genetics* / Q000473:pathology; D059506:Telomere Shortening / Q000235:genetics; D000071857:Tumor Suppressor p53-Binding Protein 1
chemical_list: D019313:BRCA1 Protein; D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D006570:Heterochromatin; D034904:Lamin Type A; C498302:Trp53bp1 protein, mouse; D000071857:Tumor Suppressor p53-Binding Protein 1; D051135:Rad51 Recombinase
keywords: DNA repair; HGPS; chromatin; genomic instability; lamins; telomeres