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Title: The molecular basis of central element assembly within the synaptonemal complex during meiosis
Author: Salmon, Lucy Jennifer
ISNI:       0000 0004 9354 5092
Awarding Body: Newcastle University
Current Institution: University of Newcastle upon Tyne
Date of Award: 2019
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In the first meiotic division, homologous chromosomes must pair, synapsis, exchange genetic material through crossing over, and then segregate to allow haploid germ cell production. This challenging process is triggered by double-strand break (DSB) induction, which activates repair machinery to generate recombination intermediates between homologues. These physical tethers guide synaptonemal complex (SC) assembly; a supramolecular lattice producing continuous synapsis between homologues. The SC provides the necessary three-dimensional structure for recombination intermediate resolution, including crossover formation, therefore is essential for meiotic division and thereby fertility. The underlying mammalian SC lattice is provided through self-assembly of SYCP1. However, a further five central element (CE) proteins are essential for full SC structure and function in vivo. A direct biochemical interaction was identified between human SYCP1 and CE protein SYCE3, revealing the sole physical link between SYCP1 and the CE. Light and Xray scattering experiments elucidated conformational re-modelling upon interacting, with SYCE3 modifying the SYCP1 lattice to achieve its regular incorporation. SYCE3 further interacts with, and thereby recruits, other CE proteins thus acting as a molecular glue for SC maturation. The CE SYCE2-TEX12 complex is recruited via SYCE3 binding, and undergoes fibrous assembly to achieve SC elongation. Through identification of two mutants that separately block SYCE2-TEX12 4:4 complex formation and its fibrous assembly, coupled with detailed biophysical analysis and two X-ray crystal structures, a structural model is proposed for the SYCE2-TEX12 complex and the mechanism of fibrous assembly. Analysis of mammalian SC assembly in vivo is severely hampered by the lack of a genetically tractable system. Whilst SC structure is conserved in yeast, protein constituents show no overt sequence similarity; thus, structural studies of the yeast SC were initiated to understand the underlying conservation. Yeast CE proteins, Ecm11-Gmc2, form a constitutive 2:2 complex with a structural model presented based upon solution scattering studies.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available