Staff Profile

The molecular basis of mammalian meiosis

The structure and function of the human synaptonemal complex

Our research aims to uncover the molecular basis of mammalian meiosis, with a particular focus on meiotic chromosome structure and the mechanistic basis of meiotic recombination and crossover formation. In the first meiotic division, homologous chromosome pairs are held together in synapsis by a 'zipper'-like protein assembly, the synaptonemal complex (SC). The three-dimensional architecture of the SC imposes a unique structure upon meiotic chromosomes and also provides the physical framework for meiotic recombination and crossover formation. These processes are achieved through homologous recombination-mediated DNA double-strand break repair pathways, are entirely dependent on the correct assembly of the SC, and are essential for fertility and prevention of aneuploidy. We aim to elucidate the molecular structure of the human SC, its interaction with chromosomal DNA, and how it interacts with DNA repair factors to achieve recombination and crossover formation.

We adopt a biochemical and structural biology approach to tackling this challenging and fundamental problem of cellular function. Our primary research techniques are biochemistry, biophysics (including SEC-MALS and electron microscopy) and X-crystallography, which we use to study recombinantly produced components and multi-component assemblies of the human SC.

Ultimately, we 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.

Selected publications:

Dunce, J.M., Dunne, O.M., Ratcliff, M., Millan, C., Madgwick, S., Usόn, I. & Davies, O.R. (2018) Structural basis of meiotic chromosome synapsis through SYCP1 self-assembly. Nature Structural & Molecular Biology 25, 557-569.

Dunce, J.M., Milburn, A.E., Manickam, G., da Cruz, I., Sen, L.T., Benavente, R. & Davies, O.R. (2018) Structural basis of meiotic telomere attachment to the nuclear envelope by MAJIN-TERB2-TERB1. Nature Communications, 9, 5355.

Davies OR, Forment JV, Sun M, Belotserkovskaya R, Coates J, Galanty Y, Demir M, Morton CR, Rzechorzek NJ, Jackson SP, Pellegrini L. (2015) CtIP tetramer assembly is required for DNA-end resection and repair. Nature Structural and Molecular Biology, 22, 150-157

Syrjanen, Pellegrini & Davies (2014) A Molecular Model for the Role of SYCP3 in Meiotic Chromosome Compaction; eLife 3, e02963

Current Lab Members:

James Dunce (Research Assistant and PhD student)

Orla Dunne (Postdoctoral Research Associate)

Gurusaran Manickam (PhD student)

Amy Milburn (PhD student)

Chandni Ravindan  (PhD student - joint with Amy MacQueen, Wesleyan University, Connecticut, USA)

Lab alumni

Vincentius Aji Jatikusumo (Undergraduate student - 2015)

Katie Boothby (MSci student - 2015-2016)

Matthew Ratcliff (MRes student and Research Assistant - 2015-2016)

Lucy Salmon (PhD student) 

Urszula McClurg (Faculty Research Fellow)

Lee Sen (MRes student)

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PhD Positions Available

PhD studentship in Biochemistry and Structural Biology – The molecular structure and function of the synaptonemal complex in chromosome synapsis and recombination during meiosis.

Application deadline 11th January 2019. For more details and to apply please follow this link.

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• Levasseur MD, Thomas C, Davies OR, Higgins JMG, Madgwick S. Aneuploidy in oocytes is prevented by sustained CDK1 activity through degron masking in cyclin B1. Developmental Cell 2019, 48, 1-18.
• Dunne OM, Davies OR. Molecular structure of human synaptonemal complex protein SYCE1. Chromosoma : Biology of the Nucleus 2019, 128(3), 223–236.
• Dunce JM, Dunne OM, Ratcliff M, Millán C, Madgwick S, Usón I, Davies OR. Structural basis of meiotic chromosome synapsis through SYCP1 self-assembly. Nature Structural & Molecular Biology 2018, 25(7), 557-569.
• Dunce JM, Milburn AE, Gurusaran M, Cruz Id, Sen LT, Benavente R, Davies OR. Structural basis of meiotic telomere attachment to the nuclear envelope by MAJIN-TERB2-TERB1. Nature Communications 2018, 9, 5355.
• Syrjanen JL, Heller I, Candelli A, Davies OR, Peterman EJG, Wuite GJL, Pellegrini L. Single-Molecule observation of DNA compaction by meiotic protein SYCP3. eLife 2017, 6, e22582.
• Gomez L, Felipe-Medina N, Sanchez-Martin M, Davies OR, Ramos I, Garcia-Tunon I, de Rooij DG, Dereli I, Toth A, Barbero JL, Benavente R, Llano E, Pendas AM. C14ORF39/SIX6OS1 is a constituent of the synaptonemal complex and is essential for mouse fertility. Nature Communications 2016, 7, 13298.
• Carroll B, Maetzel D, Maddocks ODK, Otten G, Ratcliff M, Smith GR, Dunlop EA, Passos JF, Davies OR, Jaenisch R, Tee AR, Sarkar S, Korolchuk VI. Control of TSC2-Rheb signaling axis by arginine regulates mTORC1 activity. eLife 2016, 5, e11058.
• Davies OR, Forment JV, Sun M, Belotserkovskaya R, Coates J, Galanty Y, Demir M, Morton CR, Rzechorzek NJ, Jackson SP, Pellegrini L. CtIP tetramer assembly is required for DNA-end resection and repair. Nature Structural and Molecular Biology 2015, 22, 150-157.
• Syrjänen JL, Pellegrini L, Davies OR. A molecular model for the role of SYCP3 in meiotic chromosome organisation. eLife 2014, 3, e02963.
• Davies OR, Lin C-Y, Radzisheuskaya A, Zhou X, Taube J, Blin G, Waterhouse A, Smith AJH, Lowell S. Tcf15 Primes Pluripotent Cells for Differentiation. Cell Reports 2013, 3(2), 472-484.
• Davies OR, Maman JD, Pellegrini L. Structural analysis of the SYCE2-TEX12 complex provides molecular insights into synaptonemal complex assembly. Open Biology 2012, 2(7), 120099.
• D'Arcy S, Davies OR, Blundell TL, Bolanos-Garcia VM. Defining the molecular basis of BubR1 kinetochore recruitment and APC/C-Cdc20 inhibition. Journal of Biological Chemistry 2010, 285(19), 14764-14776.
• Li Y, Chirgadze DY, Bolanos-Garcia VM, Sibanda BL, Davies OR, Ahnesorg P, Jackson SP, Blundell TL. Crystal structure of human XLF/Cernunnos reveals unexpected differences from XRCC4 with implications for NHEJ. EMBO Journal 2008, 27(1), 290-300.
• Davies OR, Pellegrini L. Interaction with the BRCA2 C terminus protects RAD51-DNA filaments from disassembly by BRC repeats. Nature Structural and Molecular Biology 2007, 14(6), 475-483.
• Shivji MKK, Davies OR, Savill JM, Bates DL, Pellegrini L, Venkitaraman AR. A region of human BRCA2 containing multiple BRC repeats promotes RAD51-mediated strand exchange. Nucleic Acids Research 2006, 34(14), 4000-4011.
• Blundell TL, Davies OR, Chirgadze D, Furnham N, Pellegrini L, Sibanda BL. Multiprotein Systems As Targets for Drug Discovery: Opportunities and Challenges. Beilstein-Institut 2006.
• Bolanos-Garcia VM, Davies OR. Structural analysis and classification of native proteins from E. coli commonly co-purified by immobilised metal affinity chromatography. Biochimica et Biophysica Acta 2006, 1760(9), 1304-1313.
• Blundell TL, Sibanda BL, Montalvao RW, Brewerton S, Chelliah V, Worth CL, Harmer NJ, Davies OR, Burke D. Structural biology and bioinformatics in drug design: opportunities and challenges for target identification and lead discovery. Philosophical Transactions of the Royal Society B: Biological Sciences 2006, 361(1467), 413-23.
• Doré AS, Furnham N, Davies OR, Sibanda BL, Chirgadze DY, Jackson SP, Pellegrini L, Blundell TL. Structure of an Xrcc4–DNA ligase IV yeast ortholog complex reveals a novel BRCT interaction mode. DNA Repair 2006, 5(3), 362-368.
• Yang Y, Denton H, Davies OR, Smith-Jackson K, Kerr H, Herbert A, Barlow PN, Pickering MC, Marchbank KJ. An Engineered Complement Factor H Construct for Treatment of C₃ Glomerulopathy. Journal of the American Society of Nephrology 2018, 29(6), 1649-1661.