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dc.contributor.advisorSchirmer, Eric
dc.contributor.advisorEarnshaw, Bill
dc.contributor.authorZuleger, Nikolaj
dc.date.accessioned2012-07-25T09:28:26Z
dc.date.available2012-07-25T09:28:26Z
dc.date.issued2012-06-22
dc.identifier.urihttp://hdl.handle.net/1842/6194
dc.description.abstractThe nuclear envelope is a complex double membrane system that separates the activities of the nuclear and cytoplasmic compartments. A recent explosion in the number of proteins associated with this subnuclear organelle together with it now being linked to over 2 dozen diseases indicates the importance of better understanding its functional organisation. This thesis addresses two important questions for this: how do integral proteins of the nuclear envelope get to their sites of function and do any of these proteins direct genome organisation? To address the first question I used FRAP and photoactivation methods to find that different proteins use at least 4 distinct mechanisms to reach the inner nuclear membrane. Some appeared to be translocated by simple unaided lateral diffusion in the membrane while others needed Ran GTPase activity, others ATP, some others were aided by phenylalanine/glycines (FGs). Both Ran and FG mechanisms required the nucleoporin Nup35, albeit the mechanisms appeared to be completely independent of one another. To investigate the role of the nuclear envelope in genome organization, I screened for nuclear envelope proteins that reposition particular chromosomes to the nuclear periphery, finding five with this function. Interestingly, all of the proteins with this effect are tissuespecific. Depletion of two liver-specific nuclear envelope proteins reversed their effects on a specific chromosome for positioning with respect to the nuclear periphery. Finally, exogenous expression of these proteins in tissue culture cells caused induction of genes involved in differentiation pathways.en
dc.contributor.sponsorWellcome Trusten
dc.language.isoenen
dc.publisherThe University of Edinburghen
dc.relation.hasversionKorfali, N., G.S. Wilkie, S.K. Swanson, V. Srsen, D.G. Batrakou, E.A. Fairley, P. Malik, N. Zuleger, A. Goncharevich, J. de Las Heras, D.A. Kelly, A.R. Kerr, L. Florens, and E.C. Schirmer. 2010. The leukocyte nuclear envelope proteome varies with cell activation and contains novel transmembrane proteins that affect genome architecture. Mol Cell Proteomics. 9:2571-2585.en
dc.relation.hasversionMalik, P., N. Korfali, V. Srsen, V. Lazou, D.G. Batrakou, N. Zuleger, D.M. Kavanagh, G.S. Wilkie, M.W. Goldberg, and E.C. Schirmer. 2010. Cell-specific and lamin-dependent targeting of novel transmembrane proteins in the nuclear envelope. Cell Mol Life Sci. 67:1353-1369.en
dc.relation.hasversionMalik, P., N. Zuleger, and E.C. Schirmer. 2009. Transport of inner nuclear membrane proteins. In Nuclear Transport. R. Kehlenbach, editor. Landes Bioscience, Austin. 133-145.en
dc.relation.hasversionWilkie, G.S., N. Korfali, S.K. Swanson, P. Malik, V. Srsen, D.G. Batrakou, J. de las Heras, N. Zuleger, A.R. Kerr, L. Florens, and E.C. Schirmer. 2011. Several novel nuclear envelope transmembrane proteins identified in skeletal muscle have cytoskeletal associations. Mol Cell Proteomics. 10:M110 003129.en
dc.relation.hasversionZuleger, N., D.A. Kelly, A.C. Richardson, A.R. Kerr, M.W. Goldberg, A.B. Goryachev, and E.C. Schirmer. 2011a. System analysis shows distinct mechanisms and common principles of nuclear envelope protein dynamics. J Cell Biol. 193:109-123.en
dc.subjectnuclear envelopeen
dc.titleInner nuclear membrane proteins: targeting and influence on genome organizationen
dc.typeThesis or Dissertationen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD Doctor of Philosophyen


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