Altered chromatin organization and SUN2 localization in mandibuloacral dysplasia are rescued by drug treatment.
Mandibuloacral dysplasia type A (MADA) is a rare laminopathy characterized by growth retardation, craniofacial anomalies, bone resorption at specific sites including clavicles, phalanges and mandibula, mottled cutaneous pigmentation, skin rigidity, partial lipodystrophy, and insulin resistance. The disorder is caused by recessive mutations of the LMNA gene encoding for A-type lamins. The molecular feature of MADA consists in the accumulation of the unprocessed lamin A precursor, which is detected at the nuclear rim and in intranuclear aggregates. Here, we report the characterization of prelamin A post-translational modifications in MADA cells that induce alterations in the chromatin arrangement and dislocation of nuclear envelope-associated proteins involved in correct nucleo-cytoskeleton relationships. We show that protein post-translational modifications change depending on the passage number, suggesting the onset of a feedback mechanism. Moreover, we show that treatment of MADA cells with the farnesyltransferase inhibitors is effective in the recovery of the chromatin phenotype, altered in MADA, provided that the cells are at low passage number, while at high passage number, the treatment results ineffective. Moreover, the distribution of the lamin A interaction partner SUN2, a constituent of the nuclear envelope, is altered by MADA mutations, as argued by the formation of a highly disorganized lattice. Treatment with statins partially rescues proper SUN2 organization, indicating that its alteration is caused by farnesylated prelamin A accumulation. Given the major role of SUN1 and SUN2 in the nucleo-cytoskeleton interactions and in regulation of nuclear positioning in differentiating cells, we hypothesise that mechanisms regulating nuclear membrane-centrosome interplay and nuclear movement may be affected in MADA fibroblasts.
Institute of Molecular Genetics, Unit of Bologna IOR, National Research Council of Italy-CNR, Via di Barbiano 1/10, 40136 Bologna, Italy.
Daria
D
Camozzi
Maria Rosaria
MR
D'Apice
Elisa
E
Schena
Vittoria
V
Cenni
Marta
M
Columbaro
Cristina
C
Capanni
Nadir M
NM
Maraldi
Stefano
S
Squarzoni
Michela
M
Ortolani
Giuseppe
G
Novelli
Giovanna
G
Lattanzi
D030981:Acro-Osteolysis / Q000188:drug therapy* / Q000503:physiopathology*; D015153:Blotting, Western; D002478:Cells, Cultured; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects* / Q000235:genetics; D005347:Fibroblasts / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D034904:Lamin Type A; D008060:Lipodystrophy / Q000188:drug therapy* / Q000503:physiopathology*; D008148:Lovastatin / Q000494:pharmacology*; D008334:Mandible / Q000002:abnormalities / Q000503:physiopathology; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D009685:Nuclear Envelope / Q000378:metabolism; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics; D011498:Protein Precursors / Q000737:chemistry / Q000235:genetics; D011499:Protein Processing, Post-Translational; D012867:Skin / Q000166:cytology
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D034904:Lamin Type A; D008565:Membrane Proteins; D009687:Nuclear Proteins; D011498:Protein Precursors; C413025:SUN2 protein, human; C090764:prelamin A; D008148:Lovastatin