The ubiquitous Structural Maintenance of Chromosome (Smc) proteins play essential roles in chromosome condensation, segregation, DNA recombination and repair, and gene regulation. The mechanisms by which they carry out such processes are unknown. Errors in Smc function can have catastrophic consequences, and can cause the molecular defects behind human genetic diseases such as trisomies and malignant tumour development. Segregation defects during meiosis are also the cause of approximately one third of spontaneous foetal abortions and are thus a major cause of infertility in humans.
This project aims to resolve the molecular architecture of Smc complexes, and determine their mechanism of function. Using the high-resolution method of X-ray crystallography we will resolve how an essential proteins called kleisin interact with Smc proteins to produce a functional complex that associates with the DNA. Using a novel second approach, direct visualisation of the Smc/kleisin complex interacting with DNA by cryo-electron microscopy will reveal the mechanism by which the conserved family of Smc and kleisin proteins exert their topological functions on chromosomes.
This research will significantly impact on the understanding of fundamental processes of chromosome maintenance and will have critical implications in the identification of factors contributing to the development of cancer and human infertility. The results from this research will eventually assist in the development of new therapies for treating major genetic defects. This research will foster scientific collaboration between the EU and Australia. In a mutually beneficial research co-operation, the Host (MRC-LMB, Cambridge, UK) is able to provide unique training opportunities (particularly in the field of structural biology) and career development for the Fellow carrying out this research, which will assist the Fellow in pursuing a career investigating the function of fundamental protein machineries.
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