Reference : PhD Manuel Mendoza
Proper coordination of cytokinesis with chromosome segregation is essential to maintain genomic stability during cell proliferation. Chromosome segregation errors, such as lagging chromosomes and anaphase chromatin bridges, pose a dramatic danger to dividing cells. The cell division apparatus can damage the unsegregated DNA, resulting in aneuploidy and cell death. At the level of the organism, these errors can directly lead to severe pathologies such as cancer.
We study cellular mechanisms that prevent DNA damage in cells with chromatin bridges, such as those caused by DNA replication stress, a condition associated with many cancers. The “NoCut” abscission checkpoint inhibits completion of cytokinesis in response to anaphase chromatin bridges. NoCut depends on the activity of the kinase Aurora-B, which localizes to spindle midzone microtubules during chromosome segregation, and detects the presence of lagging DNA in the cell division plane. In response to DNA bridges, Aurora-B inhibits the cleavage of the plasma membrane at the end of cytokinesis – a process termed abscission – and thus prevents bridge damage.
The discovery of the NoCut checkpoint revealed that cells are able to sense the presence of chromatin bridges and in response, delay completion of cell division. However, the molecular mechanism allowing cells to detect the presence of DNA bridges is still unknown. The student in charge of this project will address this question through a combination of live cell imaging, genetics and biochemistry, using budding yeast as a model system, and studying the relevance of new discoveries in mammalian non-transformed and cancer cells. Results of these studies will elucidate the NoCut molecular mechanism and establish its role in cancer progression.
Date limite de candidature : 1 novembre 2018