The molecular structure and function of the synaptonemal complex in chromosome synapsis and recombination during meiosis

Meiosis, the process of reductive cell division, is essential for fertility and genetic diversity in all sexually reproducing organisms. At the centre of this process is the synaptonemal complex (SC), a protein superstructure that acts a molecular ‘zipper’ to bind together homologous chromosomes along their entire length. The three-dimensional architecture of the SC imposes the necessary chromosomal structure and provides the physical framework for meiotic recombination and crossover formation. These processes are achieved through homologous recombination-mediated DNA double-strand break repair pathways, and are essential for fertility. Defects in synaptonemal complex formation lead to infertility, recurrent miscarriage and aneuploidies such as Down’s syndrome, in addition to germline cancers. However, whilst the protein building blocks of the synaptonemal complex have been identified in both humans and yeast, the structure of the complex and its molecular function in meiosis remain unknown. This PhD project aims to elucidate the molecular structures of the principal yeast SC components Zip1 and Ecm11-Gmc2, and to determine their mechanism of SC assembly. This will be achieved through recombinant protein purification, a range of biophysical techniques (including SEC-MALS, SEC-SAXS, CD and EM), X-ray crystallography, yeast two-hybrid and genetics, and computational bioinformatics. It will therefore involve an unprecedented level of multi-disciplinary training. We will combine the resulting molecular information with our ongoing studies on the human SC to define the underlying molecular basis for SC function across eukaryotes. This will enable us to translate directly between human and yeast systems, allowing us to exploit the genetic tractability of yeast in a manner that is directly applicable to our understanding of human fertility. Ultimately, we aim to engineer a chimeric system in which a humanised SC is assembled and functional in yeast, and thus establish a truly genetically tractable cellular system for studying a full human SC in vivo. 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 for the bioinformatics work. The project will be supervised by Dr Owen Davies (Newcastle) and Dr Dan Rigden (Liverpool), and is part of a collaboration with EM tomography, genetics and cellular biology groups within the institute and worldwide, 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 meiotic cell division, chromosomal biology and X-ray crystallography. The successful candidate will be a highly motivated individual with interests in solving fundamental molecular questions of cellular function through both practical structural biology and computational approaches.

For further information see the website: http://www.ncl.ac.uk/camb/

To apply:
Please submit a full CV and covering letter directly to [Email Address Removed]