You are here:Owen Davies' Research Interests

Owen Davies' Research Interests

I have recently moved to the Institute for Cell and Molecular Biosciences, Newcastle University as an IRES fellow. Here, I am establishing a research group focused on elucidating the structure and function of the synaptonemal complex, the molecular ‘zipper’ of homologous chromosomes during meiosis.

The synaptonemal complex as a molecular zipper of meiotic chromosomes

The reduction in chromosome number from 46 to 23 during meiotic cell division is conceptually very simple, but is in fact very challenging to achieve at the molecular level within the cell. The 23 chromosome pairs have to find each other, align, exchange genetic material, and then segregate into separate haploid daughter cells. At the centre of this process is the synaptonemal complex, an enigmatic protein super-structure that holds together homologous chromosomes, providing the necessary functional architecture for the completion of meiotic recombination and division.

During meiotic prophase I, double-strand breaks are induced at a rate of 200-400 per cell, which through homology searches by the meiotic recombination machinery, lead to the establishment of local alignments between homologous chromosomes. Once recombination intermediates are formed, the synaptonemal complex assembles by polymerising along the length of the axis, ‘zipping’ homologous chromosome pairs together with a separation of only 100 nm. It is within this structural framework that recombination is completed through either crossover or non-crossover resolution. This process is highly regulated such that all tetrads contain at least one and rarely more than two crossovers. The synaptonemal complex then dissolves, leaving crossovers as the sole physical links between homologous chromosome pairs during metaphase I, thus their correct formation is essential for the prevention of aneuploidy. Defective synaptonemal complex formation leads to meiotic failure and chromosomal segregation errors, which are associated with infertility and recurrent miscarriage, in addition with non-lethal aneuploidies such as Down’s syndrome.

The synaptonemal complex has a tripartite ribbon-like appearance at the ultrastructural level. It consists of electron dense lateral elements that coat each chromosome axis, and an electron dense central element that lies along the mid-line. These structures are held together by an array of juxtaposed transverse filaments that interdigitate, seemingly acting as the teeth of the ‘zipper’, providing a total distance of approximately 100 nm between lateral elements. In the mammalian synaptonemal complex, the transverse filament is formed by SYCP1, a long coiled coil protein that spans between central and lateral elements. The N-terminus of SYCP1 is located in the central element, along with essential components SYCE1, SYCE2, SYCE3 and TEX12. The C-terminus of SYCP1 is located in the lateral element, where it is associated with SYCP2 and SYCP3. However, despite its discovery almost 60 years ago, we still lack any molecular information regarding the structure of the synaptonemal complex and its function in meiosis.

    Adapted from Davies et. al. 2012, with EM inset reproduced from Westergaard & Wettstein 1972.

My research is directed towards defining the full three-dimensional structure of the human synaptonemal complex and the molecular basis of its function in meiosis. To achieve this, I aim to build a structural model for the synaptonemal complex piecemeal, through biochemical, biophysical and crystalllographic studies of its key protein components and complexes. As an example of this work, below is described a recent biophysical study of the SYCE2-TEX12 complex that forms a key architectural component of the central element.

Ultimately, I aim to define the molecular structure and function of the synaptonemal complex in meiosis, the mechanisms that control its dynamic assembly and disassembly in meiotic cells, and how its defective formation leads to human infertility and recurrent miscarriage. This knowledge will be essential in developing new diagnostic tools for determining the molecular basis of infertility and miscarriage, and may further lead to the development of new assisted reproduction technologies directed towards conditions for which there are currently no treatment options.

Central element: SYCE2-TEX12

In a recent study we demonstrated that central element proteins SYCE2 and TEX12 exist in a constitutive hetero-octameric complex. This structure is formed through reciprocal and likely co-operative interactions between an SYCE2 tetramer and two TEX12 dimers, such that it is equimolar (4SYCE2:4TEX12). Through EM analysis, we found that SYCE2-TEX12 hetero-octamers undergo higher order assembly into long filamentous structures that are approximately 40 nm wide, and extend in length from 300 nm to 1 um (with occasional extended structures of up to 5 um). These structures show remarkable similarity with the central element of the native mammalian synaptonemal complex. We suggest a model in which SYCE2-TEX12 hetero-octamers undergo concentration-dependent assembly, through associations of their long axes, into filamentous structures that act as key architectural components of the central element. We envisage that synaptic initiation occurs through interactions of SYCP1, SYCE1 and SYCE3 in the mid-line, with the assembly of SYCE2-TEX12 filaments mediating longitudinal growth of the central element and synaptic extension along the chromosome axis. This work is described in Davies et. al. 2012 Open Biology, 2, 120099. DOI: 10.1098/rsob.120099.

    Adapted from Davies et. al. 2012, with EM inset reproduced from Kouznetsova et. al. 2011.
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Highlights

February 2014
JBC Best paper of the year 2013 awarded to Pr. Rick Lewis
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January 2014
2014 is the year of Crystallography
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January 2014
CCP4 Study Weekend
3-5th of January, Nottingham University Read more...

Contact Info

Newcastle Structural Biology Laboratory
ICAMB, Medical School University of Newcastle Framlington place NE2 4HH, Newcastle upon Tyne, UK

Phone: (191) 222-7436
Fax: (191) 222-7424