During every cell division, the genome must accurately replicate and segregate a complete set of chromosomes into each daughter cell. Failures in chromosome segregation have severe consequences for human health, since creating cells with an inappropriate chromosome number can lead to cell death, birth defects, or cancer. The long-term goal of our research is to define the molecular machinery and mechanisms that govern chromosome segregation to ensure genomic stability. This proposal focuses on condensin protein complexes, conserved key regulators of chromosome organization and segregation. Condensins bind and reconfigure meiotic and mitotic chromosomes prior to their segregation, and are thought to do so by using ATP hydrolysis to wind DNA into large loops. We seek to understand the functions and composition of the multiple condensin complexes, which are not as straightforward as originally thought. Using the model organism C. elegans, we showed that condensin is not a simple compaction factor, but plays more complex roles in sister chromatid resolution and centromere organization. We also demonstrated the existence of two condensin complexes with overlapping components but distinct functions in mitosis and X chromosome gene regulation. It has since become clear that human cells also contain two condensins (condensin I and II) both necessary for mitosis but having distinct chromosome localization, function, and regulation. Important unanswered questions about condensins include determining the precise function each complex performs, to what extent these functions are unique or redundant, and how these functions are differentially regulated through the cell cycle and development. In preliminary studies we identified additional condensin I and II subunits, provided evidence for a condensin I that functions in chromosome segregation, and identified kinases that may tie condensin function to the cell cycle. We propose to: 1) Determine the composition and number of C. elegans complexes and identify their associated proteins. 2) Determine the distinct functions of different condensin complexes in mitosis, meiosis, and gene regulation. 3) Determine how condensin is regulated by cell cycle kinases. This research will provide insight into how cells ensure accurate distribution of the genetic material during cell division, and avoid the chromosomal errors often observed in miscarriages and solid tumors.
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