EastBio: Mechanisms of genome organisation and inheritance

A defining aspect of life is the accurate transmission of genetic information from one generation of cells to the next. During mitosis, chromosomes are reorganised dramatically into discrete cylindrical entities. Chromosome refolding facilitates disentanglement of sister-chromatids, permitting their even distribution between two daughter cells, and provides resilience to the forces of genome segregation. During genome segregation the chromosomes are captured and transported by microtubules of the mitotic spindle in a highly regulated process that ensures chromosomes are equally divided between two daughter cells. Aberrant chromosome segregation leads to aneuploidy, a hallmark of cancer and infertility, and anti-cancer drug resistance.

For successful cell division, three major properties of mitotic chromosomes are established: First, chromosomes -which are pairs of identical, sister chromatids- must remain coupled until they are evenly divided between daughter cells during anaphase. Second, sister chromatids are resolved and disentangled to ensure segregation into separate cells. Failure to disentangle chromatid pairs can result in aneuploidy and genome instability. Finally, centromeres -the attachment points that enable chromosome movement during mitosis- must withstand the forces of chromosome alignment and segregation.

In this PhD project the student will use structural biochemistry to determine the molecular basis by which key molecular machines are recruited to and organise the chromosome to resist spindle forces. The ultimate goal is to understand how chromosomes withstand the mechanical stresses of mitosis without disintegrating. 

The student will have the opportunity to learn a broad variety of key structural biochemistry techniques, including cryo-EM, X-ray crystallography, protein structure prediction, and cryo-electron tomography. High-resolution structural biological methods will be employed to obtain mechanistic insight into how centromeres are organised to promote chromosome segregation. The student will additionally have the opportunity to employ cell biological assays and single-molecule biophysical approaches to characterise the consequences of structure-guided mutations on chromosome structure and segregation.