Grant: Project Grant

Any mistake in the transmission of our genetic material is sufficient to generate genome instability, one of the strongest drivers of cancer development in humans. The overarching goal of this proposal is to uncover how living organisms ensure the accurate separation of chromosomes during cell proliferation. To achieve this objective, our team takes advantage of yeast as a simple model organism to study the regulation of chromosomes behavior during cell division. Unlike in higher organisms, genes essential for chromosome segregation can be selectively inactivated with high temporal resolution in yeast, making it possible to investigate chromosome behavior with exceptional precision. Our previous research has uncovered key mechanisms that reshape chromosome structure during cell division. These mechanisms depend on evolutionarily conserved enzymes-polo-like kinase, casein kinase, and cyclin-dependent kinase-that play central roles in normal cell division and are frequently misregulated in human cancers. We have shown that each of these enzymes modifies the chromosome-organizing factor condensin by attaching a small negatively charged group -a simple phosphate molecule- on the enzyme. Our next objective is to determine how these phosphate modifications regulate condensin during individual stages of cell division. In particular, we propose to remove the negative tags on condensin and determine how this affects the ability of cells to maintain chromosome structure and to allow effective separation of chromosomes during cell multiplication. We also want to understand how different types of tags added on condensin affect its functions at the molecular level. Ultimately, our work will have a major positive impact on human health by revealing new cellular mechanisms that underlie cancer development and reveal novel genetic vulnerabilities that may be exploited for cancer therapy.