The DNA of eukaryotic cells is contained within the nucleus and is separated from the cytoplasm by a double membrane, known as the nuclear envelope. Protein of the nuclear envelope play a critical role in the structural organization of the nucleus and also in communication between the nuclear interior and the cytoplasm. Their importance is highlighted by the fact that nuclear envelope proteins are mutated in a wide range of human inherited disorders including muscular dystrophies, lipodystrophy (fat wasting), neuropathy and premature ageing syndromes (progeria). Although over 70 nuclear envelope proteins have now been identified, their precise functions remain poorly understood. The aim of our research is to characterize the functions of nuclear envelope proteins and, through this, to gain a better understanding of how mutations in these proteins cause such diverse inherited disorders.
Research in my lab is currently focused on the SUN domain proteins, SUN1 and SUN2, that are central components of the LINC complex. This complex directly connects the nuclear envelope to the cytoskeleton and is critical for nuclear-cytoplasmic communication, playing roles in cellular mechanical integrity, mechanotransduction and nuclear positioning. These properties are particularly important in muscle fibres, which contain multiple, regularly spaced nuclei and are subjected to intense mechanical strain as the fibres repeatedly contract and relax. Much of our research is therefore centred on addressing the role of the SUN proteins in muscle development and myonuclear positioning and their involvement in muscular dystrophies and related myopathies.
The project will explore two main topics. Firstly, characterization of the basic process of muscle differentiation and the role of the LINC complex in controlling nuclear positioning in multinucleated myotubes through recruitment of centrosomal proteins and connection with the microtubule cytoskeleton. Secondly, investigating how mutations in LINC complex proteins contribute to muscle disease by impairing nuclear connection with the microtubule network.
Our lab uses state-of-the-art cell and molecular biology techniques involving the use of RNAi and lentiviral expression systems and high resolution fluorescence microscopy, including confocal and live time-lapse imaging. Training in all of these techniques will be provided, as appropriate. In addition, we have access to excellent facilities for cloning, electron microcopy and mass spectrometry.
Applications for PhD studentships are welcome from candidates who hold or expect to hold a first or upper second class degree. Informal enquiries may be sent to Dr Sue Shackleton by email at [email protected]
. To apply please complete an on-line application form at http://www.le.ac.uk/biochem/main_pages/postappformnew.html
. Further information is available from the Department’s website at http://www2.le.ac.uk/departments/biochemistry
We are an equal opportunities employer and particularly welcome applications for Ph.D. places from women, minority ethnic and other under-represented groups.
1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.