Defying Nuclear Conventions: How Molecular Innovations Drive Divergent Mechanisms of Chromosome Segregation in Parasitic Eukaryotes

The tremendous diversity of eukaryotic life can ultimately be traced back to evolutionary modifications of molecular networks that constitute cellular processes.

A major challenge in biology is to understand how such molecular modifications drive mechanistic and structural diversity while maintaining core cellular functions. A striking example of a highly divergent but essential cellular process is chromosome segregation during cell division.

At the heart of this mechanical operation are kinetochores: large protein assemblies that connect chromosomes to spindle microtubules during meiosis and mitosis.

Although kinetochore compositions of animals and fungi are largely similar, my prior work indicates extensive molecular alterations of kinetochores throughout the eukaryotic tree of life. Particularly divergent are parasites of the eukaryotic infrakingdom Alveolata.

Most employ nuclear envelope-tethered kinetochores that navigate microtubules of an extranuclear spindle to specific nuclear compartments, enabling rather funky ways of executing chromosome segregation.

To understand how such unconventional kinetochores operate, I will deploy an evolutionary cell biology approach that integrates evolutionary genomics with targeted proteomics and high-end microscopy, to interrogate the molecular architecture and function of kinetochores in the apicomplexan Toxoplasma gondii and dinoflagellate relative Perkinsus marinus; parasitic alveolates that are related to the notorious malaria-causing agent Plasmodium, and that pose a serious threat to human and animal health worldwide.

In three aims, I will (i) discover divergent and novel kinetochore components of parasitic alveolates by comparative genomics and quantitative proteomics, (ii) define their subcellular locations throughout the cell cycle and reconstruct kinetochore architectures by super-resolution microscopy, and (iii) characterize their role in kinetochore function and chromosome segregation, using live cell imaging.

The results will contribute to understanding how molecular innovations drive the diversification of chromosome segregation mechanisms in eukaryotes and will provide novel opportunities to exploit parasitic adaptations of such systems to develop new therapeutic strategies.