Checkpoints delay cellcycle progression when DNA is damaged or S phase is incomplete, allowing time for repair or to complete replication. By contrast, apoptosis eliminates cells carrying irreparable genetic damage. While these interphase-specific DNA damage responses are well characterized, the mitotic response to DNA damage remains poorly understood. When checkpoints fail and genotoxic lesions persist into mitosis, cells often proceed through an aborted division in which chromosome segregation and cytokinesis fail. Following division failure, the resulting cells arrest in GOor die by apoptotic or non-apoptotic mechanisms. This """""""" mitotic catastrophe"""""""" response, which eliminates damaged cells, has been observed in systems rangingfrom human cells to fly embryos and may be a major cause of chemotherapy induced cell death in some tumors. Despite the evolutionaryconservation and potential clinical significance of mitotic catastrophe, this process has not been systematically analyzed. We have found that mitotic catastrophe in early Drosophila embryos is linked to centrosome inactivation, chromosome condensation defects, and midbody assembly failures. Further, this mitotic damage response required the Chk2 kinase tumor suppressor homologue, and Chk2 localizes to centrosomes, chromosomes, and the midbody. Our preliminarystudies strongly suggest that Chk2 is also required for mitotic catastrophe is human colorectal cancer cells. Chk2 may therefore function in a conserved mitotic catastrophe pathway that links the division machinery to the integrity of the chromosomal passengers. The goal of this proposal is to define the molecular and cellular mechanism of mitotic catastrophe through systematic cytological, biochemical and genetic studies in Drosophila and human cells.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Cell Structure and Function (CSF)
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Deatherage, James F
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University of Massachusetts Medical School Worcester
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Schools of Medicine
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Varmark, Hanne; Kwak, Seongae; Theurkauf, William E (2010) A role for Chk2 in DNA damage induced mitotic delays in human colorectal cancer cells. Cell Cycle 9:312-20
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