title: Nuclear envelope rupture is induced by actin-based nucleus confinement.
abstract: Repeated rounds of nuclear envelope (NE) rupture and repair have been observed in laminopathy and cancer cells and result in intermittent loss of nucleus compartmentalization. Currently, the causes of NE rupture are unclear. Here, we show that NE rupture in cancer cells relies on the assembly of contractile actin bundles that interact with the nucleus via the linker of nucleoskeleton and cytoskeleton (LINC) complex. We found that the loss of actin bundles or the LINC complex did not rescue nuclear lamina defects, a previously identified determinant of nuclear membrane stability, but did decrease the number and size of chromatin hernias. Finally, NE rupture inhibition could be rescued in cells treated with actin-depolymerizing drugs by mechanically constraining nucleus height. These data suggest a model of NE rupture where weak membrane areas, caused by defects in lamina organization, rupture because of an increase in intranuclear pressure from actin-based nucleus confinement.
authors.affiliation: Department of Basic Sciences, The Fred Hutchinson Cancer Research Center, Seattle, WA 98109.
authors.forename: Emily M
authors.initials: EM
authors.lastname: Hatch
authors.affiliation: Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037 hetzer@salk.edu.
authors.forename: Martin W
authors.identifier: http://orcid.org/0000-0002-2111-992X
authors.initials: MW
authors.lastname: Hetzer
mesh_terms: D000199:Actins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism; D015638:Cytochalasin D / Q000494:pharmacology; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology; D006801:Humans; D046912:Multiprotein Complexes / Q000378:metabolism; D009685:Nuclear Envelope / Q000187:drug effects / Q000378:metabolism*; D013314:Stress, Mechanical; D059008:Time-Lapse Imaging
chemical_list: D000199:Actins; D002843:Chromatin; D006576:Heterocyclic Compounds, 4 or More Rings; D046912:Multiprotein Complexes; C472645:blebbistatin; D015638:Cytochalasin D