Separase was first discovered as the protease that targets the cohesin subunit Scc1/Mcd1 for chromosome resolution thus ensuring proper chromosome segregation during cell cycle. Multiple other functional roles have been discovered since then, including apoptosis regulation, DNA damage repair and in centrosome disengagement and duplication. Separase overexpression and variation in its subcellular localization have been reported in specific types of human malignancies. Our group has already demonstrated that Separase is also required for telomere maintenance in both Drosophila and human cells. Although this function required the peptidase activity, it is independent of cohesins regulation indicating that Separase can serve different roles irrespective of modulation of cohesins. The main objective of this proposal is to gain further insights into the role of the Separase-dependent pathways in genome stability maintenance and chromatin organization beyond cohesins regulation. We propose to exploit Drosophila as a model system to address the role of separase in chromosome integrity and to identify conserved separase-regulated chromatin factors.
Understanding the new functions and the impact of Separase and Separase-associated regulatory protein abnormalities in genome stability maintenance will provide the basis for developing new diagnostic and therapeutic opportunities for genome instability syndromes and cancer, thus increasing life expectancy and raising the standard of living of people. In addition, the proposed study offers the possibility to perform molecular diagnostic tests.
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