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    Direct force probe reveals the mechanics of nuclear homeostasis in the mammalian cell

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    PNAS_2015_Neelam_5720_5.pdf
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    Authors
    Neelam, Srujana
    Chancellor, T J.
    Li, Yuan
    Nickerson, Jeffrey A.
    Roux, Kyle J.
    Dickinson, Richard B.
    Lele, Tanmay P.
    UMass Chan Affiliations
    Department of Cell and Developmental Biology
    Document Type
    Journal Article
    Publication Date
    2015-05-05
    Keywords
    Actins
    Animals
    Cell Adhesion
    Cell Line, Tumor
    Cell Membrane
    Cell Nucleus
    Cell Survival
    Cytoskeleton
    Elasticity
    Fibroblasts
    *Gene Expression Regulation
    Green Fluorescent Proteins
    *Homeostasis
    Humans
    Mice
    Micromanipulation
    Microscopy, Fluorescence
    Microtubules
    NIH 3T3 Cells
    Nuclear Envelope
    RNA, Small Interfering
    cytoskeleton
    nuclear forces
    nuclear mechanics
    nuclear positioning
    nuclear shape
    Cell Biology
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    Abstract
    How cells maintain nuclear shape and position against various intracellular and extracellular forces is not well understood, although defects in nuclear mechanical homeostasis are associated with a variety of human diseases. We estimated the force required to displace and deform the nucleus in adherent living cells with a technique to locally pull the nuclear surface. A minimum pulling force of a few nanonewtons--far greater than typical intracellular motor forces--was required to significantly displace and deform the nucleus. Upon force removal, the original shape and position were restored quickly within a few seconds. This stiff, elastic response required the presence of vimentin, lamin A/C, and SUN (Sad1p, UNC-84)-domain protein linkages, but not F-actin or microtubules. Although F-actin and microtubules are known to exert mechanical forces on the nuclear surface through molecular motor activity, we conclude that the intermediate filament networks maintain nuclear mechanical homeostasis against localized forces.
    Source
    Proc Natl Acad Sci U S A. 2015 May 5;112(18):5720-5. doi: 10.1073/pnas.1502111112. Epub 2015 Apr 21. Link to article on publisher's site.
    DOI
    10.1073/pnas.1502111112
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/26489
    PubMed ID
    25901323
    Related Resources
    Link to Article in PubMed
    Rights

    Publisher PDF posted as allowed by the publisher's author rights policy at http://www.pnas.org/site/aboutpnas/authorfaq.xhtml.

    ae974a485f413a2113503eed53cd6c53
    10.1073/pnas.1502111112
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      XIST and CoT-1 Repeat RNAs are Integral Components of a Complex Nuclear Scaffold Required to Maintain SAF-A and Modify Chromosome Architecture: A Dissertation

      Kolpa, Heather J. (2016-04-08)
      XIST RNA established the precedent for a noncoding RNA that stably associates with and regulates chromatin, however it remains poorly understood how such RNAs structurally associate with the interphase chromosome territory. I demonstrate that transgenic XIST RNA localizes in cis to an autosome as it does to the inactive X chromosome, hence the RNA recognizes a structure common to all chromosomes. I reassess the prevalent thinking in the field that a single protein, Scaffold Attachment Factor-A (SAF-A/hnRNP U), provides a single molecule bridge required to directly tether the RNA to DNA. In an extensive series of experiments in multiple cell types, I examine the effects of SAF-A depletion or different SAF-A mutations on XIST RNA localization, and I force XIST RNA retention at mitosis to examine the effect on SAF-A. I find that SAF-A is not required to localize XIST RNA but is one of multiple proteins involved, some of which frequently become lost or compromised in cancer. I additionally examine SAF-A’s potential role localizing repeat-rich CoT-1 RNA, a class of abundant RNAs that we show tightly and stably localize to euchromatic interphase chromosome territories, but release upon disruption of the nuclear scaffold. Overall, findings suggest that instead of “tethering” chromosomal RNAs to the scaffold, SAF-A is one component of a multi-component matrix/scaffold supporting interphase nuclear architecture. Results indicate that Cot-1 and XIST RNAs form integral components of this scaffold and are required to maintain the chromosomal association of SAF-A, substantially advancing understanding of how chromatin-associated RNAs contribute to nuclear structure.
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