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The molecular basis of chromosome synapsis and genetic exchange in meiosis

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  • Full or part time
    Dr O Davies
    Prof D Rigden
  • Application Deadline
    No more applications being accepted
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

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 proteinaceous molecular ‘zipper’ that synapses together homologous chromosomes and provides the three-dimensional framework for meiotic recombination and crossover formation. Defects in synaptonemal complex formation lead to infertility, recurrent miscarriage and aneuploidies such as Down’s syndrome, in addition to germline cancers. In our ongoing work, we have elucidated the crystal structure and mechanism of self-assembly of a number of SC components (e.g. Dunce et al 2018 Nature Structural and Molecular Biology; Syrjanen et al 2014 eLife). However, a significant limitation lies in our understanding of how these components assemble together into the three-dimensional structure of the mature SC. Such knowledge will be essential to understanding how the SC interfaces with and regulates the mechanics of meiotic recombination, and thus how its defects lead to infertility and miscarriage. Further, SC proteins are aberrantly expressed in many human cancers, which makes them ideal targets for anti-cancer drugs.

This PhD project aims to biochemically reconstitute portions of the human SC from recombinant protein components, and in parallel to purify the full SC from native yeast and mammalian sources. This will involve protein purification and structural analysis of complexes through circular dichroism, multi-angle light scattering, small-angle X-ray scattering and electron microscopy. We will seek to solve the structure of suitable complexes through X-ray crystallography. The protein components of the native SC will be identified by mass spectrometry and the structure of reconstituted and native SC assemblies will be determined through cryoEM tomography and single-particle reconstruction. Alongside laboratory work, an in silico approach will be adopted to model the structure of SC complexes, which are largely ‘coiled-coil’-like, and to utilise oligomeric models for X-ray crystallographic structure solution and for docking into cryoEM maps. It will therefore involve an unprecedented level of multi-disciplinary training.

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 computational work. The project will be supervised by Dr Owen Davies (Newcastle) and Dr Dan Rigden (Liverpool), and is part of a multi-disciplinary international collaboration. 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.

HOW TO APPLY
Applications should be made by emailing [Email Address Removed] with a CV (including contact details of at least two academic (or other relevant) referees), and a covering letter – clearly stating your first choice project, and optionally 2nd and 3rd ranked projects, as well as including whatever additional information you feel is pertinent to your application; you may wish to indicate, for example, why you are particularly interested in the selected project(s) and at the selected University. Applications not meeting these criteria will be rejected.
In addition to the CV and covering letter, please email a completed copy of the Additional Details Form (Word document) to [Email Address Removed]. A blank copy of this form can be found at: https://www.nld-dtp.org.uk/how-apply.
Informal enquiries may be made to [Email Address Removed]

Funding Notes

This is a 4 year BBSRC studentship under the Newcastle-Liverpool-Durham DTP. The successful applicant will receive research costs, tuition fees and stipend (£15,009 for 2019-20). The PhD will start in October 2020. 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. Please note, there are 2 stages to the application process.

References

Structural basis of meiotic chromosome synapsis through SYCP1 self-assembly. Nature Structural & Molecular Biology. 2018 25, 557-569.

Structural basis of meiotic telomere attachment to the nuclear envelope by MAJIN-TERB2-TERB1. Nature Communications. 2018 9, 5355.

A molecular model for self-assembly of the synaptonemal complex protein SYCE3. Journal of Biological Chemistry. 2019, 294 (23), 9260-9275.

CtIP tetramer assembly is required for DNA-end resection and repair. Nature Structural & Molecular Biology. 2015, 22, 150-157. https://doi.org/10.1038/nsmb.2937

A molecular model for the role of SYCP3 in meiotic chromosome organisation. eLife. 2014, 3, e02963.

Extending the scope of coiled-coil crystal structure solution by AMPLE through improved ab initio modelling. Acta Cryst D 2019, submitted

Molecular replacement using structure predictions from databases. Acta Cryst D 2019, in press

Ensembles generated from crystal structures of single distant homologues solve challenging molecular-replacement cases in AMPLE. Acta Cryst D2018 Mar 1;74(Pt 3):183-193.

Residue contacts predicted by evolutionary covariance extend the application of ab initio molecular replacement to larger and more challenging protein folds. IUCrJ. 2016 Jun 15;3(Pt 4):259-70.

AMPLE: a cluster-and-truncate approach to solve the crystal structures of small proteins using rapidly computed ab initio models. Acta Cryst D 2012 Dec;68(Pt 12):1622-31.



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