"Cohesin has numerous fundamental roles in eukaryotic chromosome biology. It promotes sister chromatid cohesion during cell division and is therefore essential for faithful duplication and segregation of genomic information, a fundamental processes for life. In addition to its canonical role in holding sister chromatids together during mitosis and meiosis, cohesin plays a role in the repair of double strand breaks and in regulating transcription. These are key processes that are often malfunctioning in cancer cells and in ageing oocytes. Defective cohesin function during meiosis may further contribute to human trisomy and age-related female infertility. Two developmental disorders, namely Cornelia de Lange and Roberts syndrome, are caused respectively by haplo-insufficiency of NIPBL (a cohesin loading factor), and homozygous loss of the acetyltransferase ESCO2 (a cohesin modifying enzyme).
This proposal aims to study functions and mechanisms of cohesin in higher eukaryotes using the fruit fly Drosophila melanogaster as a model system. This organism has major advantages for the here proposed questions: high quality imaging of chromosomes during early embryonic divisions, the possibility of microinjecting chemically modified proteins or mRNAs into early embryos or salivary glands, the existence of Rad21TEV flies created in the host laboratory whose cohesin can be rapidly removed from chromosomes by expression of TEV protease, and the existence of huge polytene chromosomes on which expression of individual genes and cohesin association can be visualized cytologically. These advantages are essential in allowing me to address the following questions: Is the hinge heterodimerisation domain the entry gate for cohesin’s loading onto chromatids? What is the mechanism and function of cohesin’s dissociation during prophase? Which roles do the prophase pathway and the cohesin-associated prophase regulator WAPL have during embryonic divisions and in regulating transcription?"
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