Accurate partitioning of the genetic material during cell division is critical for genetic stability. Defects in chromosome segregation produce aneuploidy, an unequal distribution of chromosomes between daughter cells, which is cause of developmental defects, and one of the cancer hallmarks. To ensure error-free transmission of chromosomes, feedback control systems verify that processes at each stage of the cycle have been completed before progression into the next stage. In particular, the spindle assembly checkpoint prevents initiation of anaphase until chromosomes attach properly to the spindle, whereas the NoCut checkpoint, which I identified, delays cytokinesis until chromosome segregation is complete. The discovery of NoCut, which is conserved from yeast to humans, reveals that eukaryotic cells monitor chromosome segregation during anaphase. The molecular mechanisms of this, and potentially other anaphase feedback controls remain obscure.
The goal of this proposal is to achieve a detailed understanding of the mechanisms coordinating chromosome segregation and cytokinesis. Key to this task will be the experimental manipulation of chromosome architecture in budding yeast, which allows the generation of cells with extra long chromosome arms. Using this strategy, we have already uncovered one novel feedback system, which monitors axial chromosome compaction during anaphase. We will investigate this and other anaphase controls through a multidisciplinary approach, which combines genetic techniques with state-of-the-art live cell microscopy, genomics and proteomics. We will characterize the feedback mechanism controlling chromosome compaction, and the molecular basis of chromosome segregation errors during anaphase. The relevance of these novel processes will be confirmed by analysis of cell division in animal cells and in a Drosophila tumour model. These approaches will advance our understanding of how eukaryotic cells prevent aneuploidy and tumorigenesis.
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