Structural and Mechanistic Characterisation of Regulatory Interaction Networks Essential for High Fidelity Chromosome Segregation

Cell division is a fundamental biological process essential for organismal growth and repair. In a human body millions of cells undergo division every second and every single time the genetic information which is in the form of chromosomes needs to be accurately distributed to the newly formed daughter cells. Understanding the molecular mechanisms of accurate chromosome segregation is crucial as defects in this process often result in daughter cells with inappropriate chromosome number, a state called aneuploidy which is a hallmark of cancer. Some of the key molecular processes essential for error-free chromosome segregation are: (i) physical attachment of chromosomes to the mitotic spindle, (ii) holding the sister chromatids together until all chromosomes (sister chromatid pairs) establish biorientation, where sister chromatids attach to microtubules emanating from opposite spindle poles, and (iii) timely segregation of sister chromatids to the daughter cells. These processes are tightly regulated by intricate protein interaction networks involving several multi-subunit protein assemblies. However, a precise molecular understanding of how these key players interact with and regulate each other remains unclear. This project will employ an integrative structural modelling approach by combining experimental structural biology methods, such as cryogenic electron microscopy (cryoEM), X-ray crystallography and cross-linking mass spectrometry (CLMS), with computational techniques including ab-initio structure prediction, molecular docking, multiscale modelling and molecular dynamics simulations. These structural analyses will allow us to perturb specific intermolecular interactions in vitro and in human cell lines (functional rescue assays) to evaluate the roles of specific intermolecular interactions in achieving accurate chromosome segregation. This integrative structure-function approach will provide novel mechanistic insights into the regulation of chromosome...