Chromosome choreography by LINC complex coiled-coil proteins in mammalian meiosis (Newcastle)
Meiosis, the process of reductive cell division, is essential for fertility and genetic diversity in all sexually reproducing organisms. Errors in this process lead to infertility, miscarriage and genetic disorders such as Down’s syndrome, and can also generate germ cell cancers. To achieve successful reductive division requires an elaborate cellular process of chromosome ‘choreography’ during meiotic prophase. Homologous chromosome pairs are bound together in synapsis and then move rapidly throughout the cell in order to position them appropriately for metaphase and the subsequent segregation of homologues into haploid daughter cells. This process is mediated by the cellular cytoskeleton, which moves chromosomes around the cell through contacts with the telomeric chromosome ends that are provided by a LINC (linker of nucleoskeleton and cytoskeleton) complex formed by components SUN1 and KASH5. These elongated ‘coiled-coil’-containing proteins are essential for meiotic division, with disruption of KASH5 in mice leading to complete infertility. However, we currently have no molecular understanding of its function and how it interacts with both telomeres and the cytoskeleton. This PhD project will adopt a multi-disciplinary approach to determine the molecular structure of the SUN1-KASH5 complex and its mechanism of interaction with telomeres and the cytoskeleton. It will couple laboratory-based experimental work in protein biochemistry, biophysics and X-ray crystallography, with computational work aimed at further developing methods for solving elongated ‘coiled-coil’-containing protein structures. It will therefore provide an unprecedented level of multi-disciplinary training in both practical protein structural biology and computational crystallographic methods development. The PhD studentship is cross-institutional, and will be based primarily at Newcastle University, with Liverpool University hosting an extended rotation period and providing support as necessary throughout. The project will be supervised by Dr Owen Davies (Newcastle) and Dr Dan Rigden (Liverpool). This project is part of a collaboration with EM tomography, genetics and cellular biology groups in Newcastle, Würzburg and California, with whom we will test our biochemical and crystallographic findings in cellular models. This project should result in highly publishable and high impact research findings in the fields of cell division, chromosomal biology and X-ray crystallography.
For further information see the website: http://www.ncl.ac.uk/camb/
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This is a 4 year BBSRC studentship under the Newcastle-Liverpool-Durham DTP. The successful applicant will receive research costs, tuition fees and stipend (£14,057 for 2015-16). The PhD will start in September 2016. Applicants should have, or be expecting to receive, a 2.1 Hons degree (or equivalent) in a relevant subject. EU candidates must have been resident in the UK for 3 years in order to receive full support. There are 2 stages to the application process.
Syrjänen JL, Pellegrini L, Davies OR. (2014) A molecular model for the role of SYCP3 in meiotic chromosome organisation. eLife 3:e02963.