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All organisms have mechanisms to ensure that cells produced from mitotic and meiotic divisions contain the proper number of chromosomes. The cell monitors that chromosomes are copied exactly once and then distributed correctly to daughter cells. This is critical since cells containing an incomplete chromosome complement can be unviable or have abnormal growth phenotypes. In humans, inaccurate chromosome segregation during mitosis is associated with cancer; inaccurate chromosome segregation in meiosis is associated with spontaneous miscarriage, as well as genetic defects such as Downs (trisomy 21), Turner (XO), and Klinefelter (XXY) Syndrome. Many of these mechanisms are conserved from budding yeast to man. Due to the ease of genetic manipulations in budding yeast, we mainly use S. cerevisiae as our model organism. My research program uses genomics, genetics, molecular biology, and biochemistry to study mechanisms that contribute to the fidelity of chromosome distribution, in particular, 1) chromosome cohesion and 2) centromere/kinetochore function, formation and maintenance. Chromosome cohesion Inheritance of the correct number of chromosomes following cell division is dependent on chromosome cohesion. As DNA replicates, the cell establishes a molecular memory of sister chromatids using a protein complex called cohesin. Cohesin binds to both sister chromatids and ensures that they remain together until they are required to separate into daughter cells at the metaphase-to-anaphase transition. We have used DNA microarrays to produce a genome-wide map of cohesin during mitosis and meiosis in the S. cerevisiae genome. Although there does not appear to be a consensus sequence for cohesin binding, analysis of the map reveals unexpected correlations between cohesin association and genome features such as sequence, chromosome structure and transcriptional status. We are currently studying the dynamic nature of the cohesin complex and its relationship to chromatin and transcription. We are also studying the relationship between cohesion and DSB repair in meiosis. Centromeres and kinetochores Every eukaryotic cell studied to date contains a specialized histone variant that is incorporated into nucleosomes specifically at centromeres. This variant, known as Cse4 in budding yeast and more generally as CENP-A, is essential for marking the spot for kinetochore formation. Microtubules attach to kinetochores and help segregate chromosomes upon cell division. We are interested in particular how Cse4/CENP-A-containing chromatin is established and maintained in the genome. We have identified a Cse4-interacting protein, Scm3, as one factor that contributes to the formation and maintenance of centromeric chromatin. We are actively pursuing experiments that will help us understand how this factor functions in centromeric chromatin formation. Because of the unbiased nature of genomics, we hope to discover unexpected insights into the processes that ensure a perfect chromosome complement following mitotic and meiotic cell divisions. These studies should also help reveal the interplay between these mechanisms, and potentially reveal other cellular mechanisms that enhance the fidelity of chromosome distribution. Our results will help us evaluate current models for the function of centromeres, recombination, and chromosome cohesion in chromosome segregation, and will have broader implications for roles of these factors in chromosome structure. Academic Appointment: Assistant Professor, Department of Biochemistry & Molecular Biology, The University of Kansas School of Medicine Selected publications |
Gerton
Lab