title: Repetitive disruptions of the nuclear envelope invoke temporary loss of cellular compartmentalization in laminopathies.
abstract: The nuclear lamina provides structural support to the nucleus and has a central role in nuclear organization and gene regulation. Defects in its constituents, the lamins, lead to a class of genetic diseases collectively referred to as laminopathies. Using live cell imaging, we observed the occurrence of intermittent, non-lethal ruptures of the nuclear envelope in dermal fibroblast cultures of patients with different mutations of lamin A/C. These ruptures, which were absent in normal fibroblasts, could be mimicked by selective knockdown as well as knockout of LMNA and were accompanied by the loss of cellular compartmentalization. This was demonstrated by the influx of cytoplasmic transcription factor RelA and regulatory protein Cyclin B1 into the nucleus, and efflux of nuclear transcription factor OCT1 and nuclear structures containing the promyelocytic leukemia (PML) tumour suppressor protein to the cytoplasm. While recovery of enhanced yellow fluorescent protein-tagged nuclear localization signal in the nucleus demonstrated restoration of nuclear membrane integrity, part of the mobile PML structures became permanently translocated to the cytoplasm. These satellite PML structures were devoid of the typical PML body components, such as DAXX, SP100 or SUMO1. Our data suggest that nuclear rupture and loss of compartmentalization may add to cellular dysfunction and disease development in various laminopathies.
authors.affiliation: Department of Molecular Cell Biology, CARIM-School for Cardiovascular Diseases, Maastricht University Medical Center, PO Box 616, NL-6200 MD Maastricht, The Netherlands.
authors.forename: Winnok H
authors.initials: WH
authors.lastname: De Vos
authors.forename: Frederik
authors.initials: F
authors.lastname: Houben
authors.forename: Miriam
authors.initials: M
authors.lastname: Kamps
authors.forename: Ashraf
authors.initials: A
authors.lastname: Malhas
authors.forename: Fons
authors.initials: F
authors.lastname: Verheyen
authors.forename: Juliën
authors.initials: J
authors.lastname: Cox
authors.forename: Erik M M
authors.initials: EM
authors.lastname: Manders
authors.forename: Valerie L R M
authors.initials: VL
authors.lastname: Verstraeten
authors.forename: Maurice A M
authors.initials: MA
authors.lastname: van Steensel
authors.forename: Carlo L M
authors.initials: CL
authors.lastname: Marcelis
authors.forename: Arthur
authors.initials: A
authors.lastname: van den Wijngaard
authors.forename: David J
authors.initials: DJ
authors.lastname: Vaux
authors.forename: Frans C S
authors.initials: FC
authors.lastname: Ramaekers
authors.forename: Jos L V
authors.initials: JL
authors.lastname: Broers
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism; D002451:Cell Compartmentation; D002455:Cell Division; D003911:Dextrans / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D034904:Lamin Type A / Q000378:metabolism; D034882:Lamins / Q000378:metabolism*; D008164:Luminescent Proteins / Q000378:metabolism; D046911:Macromolecular Substances / Q000378:metabolism; D051379:Mice; D008970:Molecular Weight; D009685:Nuclear Envelope / Q000473:pathology* / Q000648:ultrastructure; D019913:Nuclear Localization Signals; D027702:Organic Cation Transporter 1 / Q000378:metabolism; D021381:Protein Transport
chemical_list: D001426:Bacterial Proteins; D003911:Dextrans; D034904:Lamin Type A; D034882:Lamins; D008164:Luminescent Proteins; D046911:Macromolecular Substances; D019913:Nuclear Localization Signals; D027702:Organic Cation Transporter 1; C054562:yellow fluorescent protein, Bacteria