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Nuclear Dynamics And Architecture

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Brian Burke

Brian Burke received his Ph.D. from Imperial College of the University of London where he carried out investigations into the molecular structure of human erythrocyte spectrin. This was followed by postdoctoral work with Graham Warren at the EMBL in Heidelberg and with Larry Gerace at Johns Hopkins University in Baltimore, Maryland. During this period he developed a longstanding interest in the structure and function of the nuclear envelope.

After a period as staff scientist at the EMBL, Dr. Burke joined the faculty of Harvard Medical School in the Department of Cell Biology. He later served as Professor of Cell Biology and Anatomy at the University of Calgary and as the Haskell Hess Professor of Cell Biology at the University of Florida College of Medicine. Since August 2009, Dr. Burke has been a Principal Investigator at the IMB.

Dr. Burke’s research focus now concerns the mechanisms by which defects in genes encoding nuclear envelope proteins, including human A-type lamins, give rise to a variety of human diseases. These include forms of muscular dystrophy, lipodystrophy and Hutchinson-Gilford progeria, a premature aging syndrome. This work has led to discoveries that reveal how nuclear structures may be integrated with cytoplasmic components and have defined the functions of new families of nuclear membrane proteins, including SUN domain proteins of the inner nuclear membrane and nesprin proteins of the outer nuclear membrane.

Together, SUN proteins and nesprins represent pairs of links in molecular chains that span the nuclear envelope and which mechanically couple nuclear structures with the cytoskleton. These SUN-nesprin pairs, which we have termed LINC complexes (for LInkers of the Nucleoskeleton and Cytoskeleton) play a crucial role in nuclear positioning and migration in a wide variety of cell types. In addition they may provide a new mode of communication between the cytoplasm and nucleus and could potentially mediate aspects of mechanotransduction.

 

 (Left) Overview of LINC complex organization. Inner nuclear membrane SUN domain proteins function as
tethers for outer nuclear membrane nesprins. Together these proteins represent links in a molecular chain
that connects nuclear components to the cytoskeleton.

(Right) Nesprin 4 (in green) is a new member of the nesprin family and has the capacity to bind kinesin,
a microtubule motor protein. Expression of nesprin 4 in HeLa cells is associated with the displacement
(indicated by the yellow arrow) of the centrosome (red) from its normal location adjacent to the nucleus.
DNA within nuclei is shown in blue.

 

 


 

Our research focus now concerns the mechanisms by which defects in genes encoding nuclear envelope proteins, including human A-type lamins, give rise to a variety of human diseases. These include forms of muscular dystrophy, lipodystrophy and Hutchinson-Gilford progeria, a premature aging syndrome. This work has led to discoveries that reveal how nuclear structures may be integrated with cytoplasmic components and have defined the functions of new families of nuclear membrane proteins, including SUN domain proteins of the inner nuclear membrane and nesprin proteins of the outer nuclear membrane.

Together, SUN proteins and nesprins represent pairs of links in molecular chains that span the nuclear envelope and which mechanically couple nuclear structures with the cytoskleton. These SUN-nesprin pairs, which we have termed LINC complexes (for LInkers of the Nucleoskeleton and Cytoskeleton) play a crucial role in nuclear positioning and migration in a wide variety of cell types. In addition they may provide a new mode of communication between the cytoplasm and nucleus and could potentially mediate aspects of mechanotransduction.


Both Sun1 and Sun2, the predominant SUN domain proteins of mammalian somatic cells, are localized to the nuclear periphery. DNA within the nucleus is shown in blue.  

(Left) LINC complex components (red), including a new nesprin-like protein, are associated
with telomeres in primary spermatocytes that are undergoing meiosis. DNA is revealed with
a blue fluorescent dye while synaptonemal complexes, the structures that link homologous
chromosome pairs, are shown in green.

(Right) Aligned stack nuclei.


Group Members

Research Fellows
Alessandra Calvi
  Xie Wei
  Martina Maric

Lee Yin Loon 
  Rajkumar Ramalingam
Postgraduate Students Loic Gazquez (ARAP)
  Anna Salter (ARAP)
Senior Research Officer 
Ye Xiaoqian
Laboratory Officer Hong Wei Liang


Lim JSY, Wright GD, Burke B, Xie W. A user-interactive algorithm quantifying nuclear pore complex distribution within the nuclear lamina network in single molecular localization microscopic image. Methods. 2018 Sep 27. pii: S1046-2023(18)30137-3. doi: 10.1016/j.ymeth.2018.09.006. Link
Sundaram GM, Ismail HM, Bashir M, Muhuri M, Vaz C, Nama S, Ow GS, Vladimirovna IA, Ramalingam R, Burke B, Tanavde V, Kuznetsov V, Lane EB, Sampath P. EGF hijacks miR-198/FSTL1 wound-healing switch and steers a two-pronged pathway toward metastasis. J Exp Med. 2017 Oct 2;214(10):2889-2900. doi: 10.1084/jem.20170354 Link
Di Pascale F, Nama S, Muhuri M, Quah S, Ismail HM, Chan XHD, Sundaram GM, Ramalingam R, Burke B, Sampath P. C/EBPβ mediates RNA polymerase III-driven transcription of oncomiR-138 in malignant gliomas. Nucleic Acids Res. 2017 Nov 10. doi: 10.1093/nar/gkx1105 Link
Gimpel P, Lee YL, Sobota RM, Calvi A, Koullourou V, Patel R, Mamchaoui K, Nédélec F, Shackleton S, Schmoranzer J, Burke B, Cadot B, Gomes ER. Nesprin-1α-Dependent Microtubule Nucleation from the Nuclear Envelope via Akap450 Is Necessary for Nuclear Positioning in Muscle Cells. Curr Biol. 2017 Oct 9;27(19):2999-3009.e9. doi: 10.1016/j.cub.2017.08.031 Link
Xie W, Burke B. Nuclear networking. Nucleus. 2017 Jul 4;8(4):323-330. doi: 10.1080/19491034.2017.1296616 Link
Dong JM, Tay FP, Swa HL, Gunaratne J, Leung T, Burke B, Manser E. Proximity biotinylation provides insight into the molecular composition of focal adhesions at the nanometer scale. Science Signaling 2016 Jun 14;9(432):rs4. doi: 10.1126/scisignal.aaf3572. Link
Xie W, Chojnowski A, Boudier T, Lim JS, Ahmed S, Ser Z, Stewart C, Burke B. A-type Lamins Form Distinct Filamentous Networks with Differential Nuclear Pore Complex Associations. Curr Biol. 2016 Oct 10;26(19):2651-2658. doi: 10.1016/j.cub.2016.07.049. Link
Chojnowski A, Ong PF, Wong ESM, Lim JSY, Mutalif RA, Navasankari R, Dutta B, Yang H, Liow YY, Sze SK, Boudier T, Wright GD, Colman A, Burke B, Stewart CL, Dreesen O. Progerin reduces LAP2α-telomere association in Hutchinson-Gilford progeria. eLife. 2015 Aug 27; 10.7554/eLife.07759 Link
Calvi A, Wong AS, Wright G, Wong ES, Han Loo T, Stewart CL, Burke B. SUN4 is essential for nuclear remodeling during mammalian spermiogenesis. Dev Biol. 2015 Sep 25. pii: S0012-1606(15)30200-1. doi: 10.1016/j.ydbio.2015.09.010. PubMed PMID: 26417726. Link
tewart CL, Burke B. The missing LINC: a mammalian KASH-domain protein coupling meiotic chromosomes to the cytoskeleton. Nucleus. 2014 Jan-Feb;5(1):3-10. doi: 10.4161/nucl.27819. Epub 2014 Jan 23. PubMed PMID: 24637401; PubMed Central PMCID: PMC4028352. Link
Burke B, Stewart CL. Functional architecture of the cell's nucleus in development, aging, and disease. Curr Top Dev Biol. 2014;109:1-52. doi: 10.1016/B978-0-12-397920-9.00006-8. Review. PubMed PMID: 24947235. Link
Horn HF, Kim DI, Wright GD, Wong ES, Stewart CL, Burke B, Roux KJ. A mammalian KASH domain protein coupling meiotic chromosomes to the cytoskeleton. J Cell Biol. 2013 Sep 30;202(7):1023-39. doi: 10.1083/jcb.201304004. Epub 2013 Sep 23. PubMed PMID: 24062341; PubMed Central PMCID: PMC3787381. Link
Burke B. PREEParing for mitosis. Dev Cell. 2013 Aug 12;26(3):221-2. doi: 10.1016/j.devcel.2013.07.018. PubMed PMID: 23948250. Link
Burke B, Stewart CL. The nuclear lamins: flexibility in function. Nat Rev Mol Cell Biol. 2013 Jan;14(1):13-24. doi: 10.1038/nrm3488. Epub 2012 Dec 5. Review. PubMed PMID: 23212477. Link
Horn HF, Brownstein Z, Lenz DR, Shivatzki S, Dror AA, Dagan-Rosenfeld O, Friedman LM, Roux KJ, Kozlov S, Jeang KT, Frydman M, Burke B, Stewart CL, Avraham KB. The LINC complex is essential for hearing. J Clin Invest. 2013 Feb;123(2):740-50. doi: 10.1172/JCI66911. Epub 2013 Jan 25. PubMed PMID: 23348741; PubMed Central PMCID: PMC3561815. Link
Burke B. It takes KASH to hitch to the SUN. Cell. 2012 May 25;149(5):961-3. doi: 10.1016/j.cell.2012.05.004. PubMed PMID: 22632963. Link
Burke, B. and Roux, K.J. (2009) Nuclei take a position: managing nuclear location. Dev. Cell 17: 587-597.
Roux, K.J., Crisp, M.L., Liu, Q., Kozlov, S., Stewart, C.L. and BURKE, B. (2009) Nesprin 4 is an outer nuclear membrane protein that can induce kinesin-mediated cell polarization. Proc. Natl. Acad. Sci. 106: 2194-2199.
Han, X., Feng, X., Rattner, J.B., Smith, H., Bose, P., Suzuki, K., Soliman, M.A., Scott, M.S., BURKE, B. and Riabowol, K.T. (2008) Tethering by lamin A stabilizes and targets the ING1 tumour suppressor. Nature Cell Biol. 10: 1333-1340.
Schermelleh, L., Carlton, P.M., Haase, S., Shao, L., Lukman, W., Kner, P., BURKE, B., Agard, D.A., Gustafsson, M.G.L., Leonhardt, H., Sedat, J.W. (2008) Subdiffraction multicolor imaging of the nuclear periphery with 3D structured illumination microscopy. Science 320: 1332-1336.
Stewart, C.L., Roux, K.J. and BURKE, B. (2007) Blurring the boundary: the nuclear envelope extends its reach. Science 318: 1408-1412.
Liu, Q., Pant�, N., Misteli, T., Elsagga, M., Crisp, M., Hodzic, D., BURKE, B*. and Roux, K. (2007) Functional association of Sun1 with nuclear pore complexes. J. Cell Biol. 178: 785-798. (* corresponding author)
BURKE, B. and Stewart, C.L. (2006) The laminopathies: the structure of the nucleus and its involvement in disease. Ann. Rev. Hum. Genet. 7: 369-405.
Ivorra, C., Kubicek, M., Sanz-Gonz醠ez, S.M., Gonz醠ez, J-M., Alvarez-Barrientos, A., O扖onnor, J-E., BURKE, B. and Andr閟, V. (2006) A mechanism of AP-1 suppression through interaction of c-Fos with lamin A/C. Genes Devel. 20: 307-320.
Crisp, M., Liu, Q., Roux, K., Rattner, J.B., Shanahan, C., BURKE, B*. Stahl, P., and Hodzic, D. (2006) Coupling of the nucleus and cytoplasm: role of the LINC complex. J. Cell Biol. 172: 41-53. (* corresponding author)
Salina, D. Enarson, P., Rattner, J.B. and BURKE, B. (2003) Nup358 integrates nuclear envelope breakdown with kinetochore assembly J. Cell Biol. 162: 991-1001.
BURKE, B.and Stewart, C. L. (2002) Life at the edge: the nuclear envelope and human disease. Nature Reviews Mol. Cell Biol. 3: 575-585.
BURKE, B. and Ellenberg, J. (2002) Remodeling the walls of the nucleus. Nature Reviews Mol. Cell Biol. 3: 487-497.
Salina, D., Bodoor, K., Eckley, D.M., Schroer, T.A., Rattner, J.B. and BURKE, B. (2002) Cytoplasmic dynein as a facilitator of nuclear envelope breakdown. Cell 108: 97-107.