The broad goal of the work proposed in this application is to understand the design principles and evolutionary dynamics of the cytokinesis pathway using the budding yeast as the model organism. Cytokinesis the physical division of a cell in two is the last critical step of cell division. The complexity and importance of this process has made cytokinesis one of the extensively studied and yet still unsolved problems in cell biology. We and others previously showed that the budding yeast utilizes an actomyosin-based contractile ring to divide, as in animal cells. This finding allows us to use this highly tractable model to understand the basic principles and molecular pathways governing cytokinesis. Whereas our previous work followed a conventional approach of classical genetic and biochemical analyses, here we propose to take a unique combination of network modeling, quantitative imaging, evolutionary analysis, and genomic and expression microarrays, to understand the design principles underlying the molecular complexity. The main questions to be answered in this study are: 1) how a complex network of molecular interactions, involving signaling molecules and cytoskeletal proteins, which occur during mitosis, ensures asymmetric cell division in a spatially and temporally precise manner;and 2) how, in response to large perturbations, this cell division system could rapidly evolve to maintain its required functionality.

Public Health Relevance

Cytokinesis is a crucial event in cell division, which is the basis for the growth and development of eukaryotic organisms. Failure in cytokinesis results in polyploidization, a common feature of cancer cells that is thought to contribute to genome instability and somatic evolution of cancer.1, 2. Asymmetric cytokinesis is also important for the generation of embryonic asymmetry and differentiation of diverse cell types3. Therefore, understanding the mechanism and regulation of cytokinsesis is important for treatment or prevention of diseases such as cancer and developmental abnormalities. 1.. Storchova, Z. &Pellman, D. From polyploidy to aneuploidy, genome instability and cancer. Nat Rev Mol Cell Biol 5, 45-54 (2004). 2.. Fujiwara, T. et al. Cytokinesis failure generating tetraploids promotes tumorigenesis in p53-null cells. Nature 437, 1043-1047 (2005). 3. Strome, S. Generation of cell diversity during early embryogenesis in the nematode Caenorhabditis elegans embryos. Int. Rev. Cyt. 114, 81-123 (1989).

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Modeling and Analysis of Biological Systems Study Section (MABS)
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Gindhart, Joseph G
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Stowers Institute for Medical Research
Kansas City
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Chen, Guangbo; Mulla, Wahid A; Kucharavy, Andrei et al. (2015) Targeting the adaptability of heterogeneous aneuploids. Cell 160:771-84
Zhu, Jin; Heinecke, Dominic; Mulla, Wahid A et al. (2015) Single-Cell Based Quantitative Assay of Chromosome Transmission Fidelity. G3 (Bethesda) 5:1043-56
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Mulla, Wahid; Zhu, Jin; Li, Rong (2014) Yeast: a simple model system to study complex phenomena of aneuploidy. FEMS Microbiol Rev 38:201-12
Mendes Pinto, InĂªs; Rubinstein, Boris; Li, Rong (2013) Force to divide: structural and mechanical requirements for actomyosin ring contraction. Biophys J 105:547-54
Potapova, Tamara A; Zhu, Jin; Li, Rong (2013) Aneuploidy and chromosomal instability: a vicious cycle driving cellular evolution and cancer genome chaos. Cancer Metastasis Rev 32:377-89
Mendes Pinto, Ines; Rubinstein, Boris; Kucharavy, Andrei et al. (2012) Actin depolymerization drives actomyosin ring contraction during budding yeast cytokinesis. Dev Cell 22:1247-60
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Chen, Guangbo; Rubinstein, Boris; Li, Rong (2012) Whole chromosome aneuploidy: big mutations drive adaptation by phenotypic leap. Bioessays 34:893-900
Zhu, Jin; Pavelka, Norman; Bradford, William D et al. (2012) Karyotypic determinants of chromosome instability in aneuploid budding yeast. PLoS Genet 8:e1002719

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