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Title: Meiotic chromosome dynamics: a structural characterisation
Authors: Dunce, James
Issue Date: 2020
Publisher: Newcastle University
Abstract: Meiotic chromosomes are bound in architecturally enforced synapsis during the first meiotic division by a proteinaceous megastructure known as the synaptonemal complex (SC). This molecular scaffold is built between paired homologues, providing a unique three-dimensional environment in which to form genetic crossovers, physical inter-homologue connections critical in ensuring equational segregation at metaphase. The SC structure represents the hallmark of meiotic division, with a striking tripartite appearance, conserved across evolution, in which chromosomally associated lateral elements are connected to a midline central element via transversal filaments. Such that the SC installs between correctly identified maternal-paternal pairs, a genome-wide, sequencebased, homology search is facilitated by rapid chromosomal movements. Cytoskeletal forces power these movements, transmitted through the nuclear envelope (NE) to the chromosome’s telomeric ends via the LINC (Linker of Nucleoskeleton and Cytoskeleton). Importantly, NE recruitment and tethering is mediated by the meiotic telomere complex, consisting of MAJIN, TERB1, and TERB2, without which meiotic progression is stalled. The works herein reveal the structural basis of synapsis in the human SC and chromosome tethering to the nuclear envelope by the meiotic telomere complex. Specifically, I report a complete biophysical characterisation of SYCP1, the transversal filament protein of the human SC, and present crystal structures which represent mechanisms of its assembly within the SC mediated by sequences at both its N-termini (which mediate midline, head-to-head, associations) and C-termini (which undergo pH dependent, back-to-back assembly on the chromosome axis). Further, we solved the crystal structure of the MAJIN-TERB2 complex and characterised its mode of DNA association providing key insights into how NE tethering is achieved. Our findings are discussed within the context of the existing molecular understanding of meiotic chromosome dynamics.
Description: Ph. D. Thesis
Appears in Collections:Institute for Cell and Molecular Biosciences

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