Sue Shackleton

Personal Details

Sue ShackletonSenior Lecturer
Sue Shackleton DepartmentMolecular and Cell Biology
Telephone: +44 (0)116 229 7058
Emailss115@le.ac.uk
Address: Lancaster Rd, LE1 7HB
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Biography

I am an Associate Professor in Molecular Cell Biology. I gained my degree in Biochemistry at the University of Oxford and remained there to study for a DPhil in Clinical Medicine, which focused on the genetics of cystic fibrosis. This work sparked my interest in inherited disorders and understanding how small changes in the human genome cause protein dysfunction and result in the myriad of disorders that occur in human populations. I undertook postdoctoral work studying the mechanism of internalization of the insulin receptor at the University of Geneva. In my second postdoctoral position, at the University of Leicester, I returned to the field of medical genetics, successfully identifying the LMNA gene as causative of familial partial lipodystrophy. This discovery has formed the foundation of my subsequent research career, in which I have studied proteins of the nuclear envelope, their roles in nuclear function and involvement in rare inherited disorders. I began my independent research career through a 5-year RCUK-funded fellowship, followed by a Lectureship at the University of Leicester.

Qualifications

  • Degree: Biochemistry BA, University of Oxford (1991)
  • Postgraduate Research Assistant in the laboratory of Professor Ann Harris, Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford (1991-1993)
  • DPhil: University of Oxford (1996)
  • Postdoctoral Research Assistant in the laboratory of Professor Jean-Louis Carpentier, Department of Morphology, University of Geneva, Switzerland (1996-1998)
  • Postdoctoral Research Fellow in the laboratory of Professor Richard Trembath, Department of Genetics, University of Leicester (1998-2005)
  • Research Councils UK Research Fellow, Department of Biochemistry, University of Leicester (2005-2010)
  • Lecturer, University of Leicester (2010 - 2013)
  • Senior Lecturer, University of Leicester (2013 - )

Teaching

I have a particular interest in teaching medical genetics, cell biology and approaches to examining protein function and disease mechanisms.

Publications

  1. 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 (2017) Current Biology, 27, 2999-3009.
  2. Zhou, C., Li, C., Zhou, B., Sun, H., Koullourou, V., Holt, I., Puckelwartz, M.J., Warren, D.T., Hayward, R., Lin, Z., Zhang, L., Morris, G.E., McNally, E.M., Shackleton, S., Rao, L., Shanahan, C.M., Zhang, Q. Novel nesprin-1 mutations associated with dilated cardiomyopathy cause nuclear envelope disruption and defects in myogenesis. (2017) Human Molecular Genetics, 26, 2258-2276.
  3. Mikolcevic, P., Isoda, M., Shibuya, H., del Barco Barrantes, I., Igea, A., Suja, J. A., Shackleton, S., Watanabe, Y. and Nebreda, A. R. Essential role of the atypical Cdk2 activator RingoA in meiotic telomere tethering to the nuclear envelope. (2016) Nature Communications, 7, 11084.
  4. Patel JT., Bottrill A., Prosser S.L., Jayaraman S., Straatman K., Fry A.M., Shackleton S. Mitotic phosphorylation of SUN1 loosens its connection with the nuclear lamina while the LINC complex remains intact. (2014) Nucleus 5, 462-473.
  5. Meinke, P., Mattioli, E., Haque, F., Antoku, S., Columbaro, M., Straatman, K.R., Worman, H.J., Gundersen, G.G., Lattanzi, G., Wehnert, M., Shackleton, S. Muscular Dystrophy-Associated SUN1 and SUN2 Variants Disrupt Nuclear-Cytoskeletal Connections and Myonuclear Organization. (2014) PLoS Genetics 10, e1004605.
  6. Watkins, R.J., Patil, R., Goult, B.T., Thomas, M.G., Gottlob, I. and Shackleton, S. A novel interaction between FRMD7 and CASK – evidence for a causal role in idiopathic infantile nystagmus. (2013) Human Molecular Genetics22, 2105-2118.
  7. Sylvius, N., Bonne, G., Straatman, K., Reddy, T., Gant, T. and Shackleton, S. MicroRNA expression profiling in patients with lamin A/C-associated muscular dystrophy. (2011) FASEB J. 25, 3966-3978.
  8. Haque F, Mazzeo, D., Patel, J.T., Smallwood, D.T., Ellis, J.A., Shannahan, C.M. and Shackleton, S. Mammalian SUN protein networks at the inner nuclear membrane and their role in laminopathy disease processes. (2010) Journal of Biological Chemistry 285, 3487-98.
  9. Mazereeuw-Hautier, J., Wilson, L.C., Mohammed, S., Smallwood, D., Shackleton, S., Atherton, D.J. and Harper, J.I. Hutchinson-Gilford Progeria syndrome: clinical findings in three patients carrying the G608G mutation in LMNA and review of the literature. (2007) British Journal of Dermatology 156, 1308-1314.
  10. Haque, F., Lloyd, D, Smallwood, D., Dent, C., Shanahan, C., Fry, A., Trembath, R. and Shackleton, S. SUN1 interacts with nuclear lamin A and cytoplasmic nesprins to provide a physical connection between the nuclear lamina and the cytoskeleton (2006) Molecular and Cellular Biology 26, 3738-3751.
  11. Shackleton, S., Smallwood, D.T., Clayton, P., Wilson, L.C., Agarwal, A. K., Garg, A. and Trembath, R.C. Compound heterozygous ZMPSTE24 mutations reduce prelamin A processing and result in a severe progeroid phenotype (2005) Journal of Medical Genetics 42, e36.
  12. Lloyd, D., Trembath, R., Shackleton, S. A novel interaction between lamin A and SREBP1: implications for partial lipodystrophy (2002) Human Molecular Genetics 11, 769-777.
  13. Shackleton, S., Hamer, I., Foti, M., Zumwald, N., Maeder, C. and Carpentier, J.-L. Role of two dileucine-type motifs in insulin receptor anchoring to microvilli (2002) Journal of Biological Chemistry 277, 43631-43637
  14. Vigouroux, C., Magré, J., Vantyghem, M.-C., Bourut, C., Lascols, O., Shackleton, S., Lloyd, D., Guerci, B., Padova, G., Valensi, P., Grimaldi, A., Piquemal, R., Touraine, P., Trembath, R., Capeau, J. Sex-determined expression of mutations in Dunnigan-type familial partial lipodystrophy and absence of coding mutations in congenital and acquired generalized lipoatrophy (2000) Diabetes 49, 1958-1962.
  15. Shackleton, S., Lloyd, D., Jackson, S., Evans, R., Niermeijer, M., Singh, B., Schmidt, H., Brabant, G., Kumar, S., Durrington, P., Gregory, S., O’Rahilly, S., Trembath, R. The LMNA gene encoding lamin A/C is mutated in partial lipodystrophy (2000) Nature Genetics 24, 152-156.

Research

My lab is interested in understanding nuclear envelope (NE) architecture and function and its role in human inherited disease. My interest in this field began as a postdoc when I was involved in identifying LMNA as the gene associated with familial partial lipodystrophy in 2000. This led me to examine the role of lamins in various laminopathies, including Hutchinson-Gilford progeria syndrome.

Having identified SUN proteins as lamin A-binding partners, the LINC complex became the focus of my research when I started my own lab in 2005. The LINC complex is comprised of two protein families: SUN and nesprin proteins, that reside at the inner and outer nuclear membranes, respectively. We contributed to characterising the central role of the LINC complex in mediating connection between the nuclear lamina and cytoskeleton, which is important for many cellular properties and functions.

My lab is currently focused on the role of the LINC complex in muscle development and function. In particular, we are interested in the role of the muscle specific nesprin-1alpha isoform in nuclear connection to the microtubule network and in the formation of a unique nuclear microtubule organizing centre. This connection controls the regular spacing of myonuclei and we are examining how defects in the connection may contribute to muscle disorders such as Emery-Dreifuss muscular dystrophy. We are also studying alternative splice variants of SUN1 that may play a role in muscle differentiation, potentially through changes in nuclear mechanics or in gene expression patterns.

Supervision

  • Formation of the nuclear microtubule organising centre (nMTOC) during myogenesis
  • Examining defects in nMTOC formation and myonuclear organisation in myopathies
  • Role of SUN1 splice variants in regulating myogenesis

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Department of Molecular and Cell Biology

T: +44(0)116 229 7038
E: MolCellBiol@le.ac.uk

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