title: Nuclear constriction segregates mobile nuclear proteins away from chromatin.
abstract: As a cell squeezes its nucleus through adjacent tissue, penetrates a basement membrane, or enters a small blood capillary, chromatin density and nuclear factors could in principle be physically perturbed. Here, in cancer cell migration through rigid micropores and in passive pulling into micropipettes, local compaction of chromatin is observed coincident with depletion of mobile factors. Heterochromatin/euchromatin was previously estimated from molecular mobility measurements to occupy a volume fraction f of roughly two-thirds of the nuclear volume, but based on the relative intensity of DNA and histones in several cancer cell lines drawn into narrow constrictions, f can easily increase locally to nearly 100%. By contrast, mobile proteins in the nucleus, including a dozen that function as DNA repair proteins (e.g., BRCA1, 53BP1) or nucleases (e.g., Cas9, FokI), are depleted within the constriction, approaching 0%. Such losses-compounded by the occasional rupture of the nuclear envelope-can have important functional consequences. Studies of a nuclease that targets a locus in chromosome-1 indeed show that constricted migration delays DNA damage.
authors: Physical Sciences Oncology Center at Penn, University of Pennsylvania, Philadelphia, PA 19104.|Molecular and Cell Biophysics Lab, University of Pennsylvania, Philadelphia, PA 19104.
authors: Jerome
authors: J
authors: Irianto
authors: Physical Sciences Oncology Center at Penn, University of Pennsylvania, Philadelphia, PA 19104.|Molecular and Cell Biophysics Lab, University of Pennsylvania, Philadelphia, PA 19104.|Graduate Group/Department of Physics and Astronomy, University of Pennsylvania, Philadelphia, PA 19104.
authors: Charlotte R
authors: CR
authors: Pfeifer
authors: Physical Sciences Oncology Center at Penn, University of Pennsylvania, Philadelphia, PA 19104.|Graduate Group/Department of Physics and Astronomy, University of Pennsylvania, Philadelphia, PA 19104.
authors: Rachel R
authors: RR
authors: Bennett
authors: Physical Sciences Oncology Center at Penn, University of Pennsylvania, Philadelphia, PA 19104.|Molecular and Cell Biophysics Lab, University of Pennsylvania, Philadelphia, PA 19104.
authors: Yuntao
authors: Y
authors: Xia
authors: Physical Sciences Oncology Center at Penn, University of Pennsylvania, Philadelphia, PA 19104.|Molecular and Cell Biophysics Lab, University of Pennsylvania, Philadelphia, PA 19104.
authors: Irena L
authors: IL
authors: Ivanovska
authors: Physical Sciences Oncology Center at Penn, University of Pennsylvania, Philadelphia, PA 19104.|Graduate Group/Department of Physics and Astronomy, University of Pennsylvania, Philadelphia, PA 19104.
authors: Andrea J
authors: AJ
authors: Liu
authors: Physical Sciences Oncology Center at Penn, University of Pennsylvania, Philadelphia, PA 19104.|Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors: Roger A
authors: RA
authors: Greenberg
authors: Physical Sciences Oncology Center at Penn, University of Pennsylvania, Philadelphia, PA 19104 discher@seas.upenn.edu.|Molecular and Cell Biophysics Lab, University of Pennsylvania, Philadelphia, PA 19104.|Graduate Group/Department of Physics and Astronomy, University of Pennsylvania, Philadelphia, PA 19104.
authors: Dennis E
authors: DE
authors: Discher
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism / Q000502:physiology*; D002843:Chromatin / Q000378:metabolism*; D022041:Euchromatin / Q000378:metabolism; D006570:Heterochromatin / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D009685:Nuclear Envelope / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism
chemical_list: D002843:Chromatin; D022041:Euchromatin; D006570:Heterochromatin; D006657:Histones; D009687:Nuclear Proteins