School of Biological and Chemical Sciences

A molecular study of mechanisms that drive aneuploidy in cancers

Supervisor: Dr Viji M. Draviam-Sastry

Project description

Aggressive cancers contain cells that display irregular number of chromosomes; this state is called aneuploidy. Aneuploidy can directly arise from errors in the process of chromosome segregation that can lead to the gain or loss of chromosomes in the daughter cells. The precise molecular lesions that cause aneuploidy in cancers has remained elusive. Our group is interested in identifying these aneuploidy promoting lesions and in understanding the immediate and long-term impact of these lesions.

To ensure the accurate segregation of human chromosomes, rope-like microtubules must properly attach to chromosomes and pull the sister chromatids apart into two equal sets. Chromosome-microtubule attachment is mediated by a macromolecular machine called the kinetochore made up of over 100 different proteins. We combine high-resolution live-cell microscopy, human cell culture and molecular biology tools to visualise how microtubules capture and pull apart chromosomes during mitosis.

The goal of the project is to understand how kinetochores work and what is the consequence of kinetochore lesions in healthy and cancerous human cells. In this project, the student will analyse the immediate and long-term fate of human cells that undergo different extents of chromosome missegregation. Mutants to induce different extents of chromosome mis-segregation (severe or subtle) will be first introduced into non-transformed healthy or transformed cancer cells. Next, the student will analsye the immediate and long-term fate using time-lapse microscopy. The findings of this project will be an important first step towards understanding whether normal and tumour cells can tolerate the burden of aneuploidy similarly. This multidisciplinary project is ideal for students interested in working at the interface of cancer and basic biology research.

Send an email to Dr Draviam-Sastry for more information.

References

  • Ochi T et al PAXX, a paralog of XRCC4 and XLF, interacts with Ku to promote DNA double-strand break repair Science 2015 347 (6218): 185-188.
  • Tamura et al., Mitosis phase-specific interactions of EB1 reveal two pools of SKAP associated with distinct mitotic outcomes. (Biology Open 2015 (4): 155-169).

See also