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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM050898-14
Application #
7535602
Study Section
Cell Structure and Function (CSF)
Program Officer
Deatherage, James F
Project Start
1995-02-01
Project End
2010-11-30
Budget Start
2008-12-01
Budget End
2010-11-30
Support Year
14
Fiscal Year
2009
Total Cost
$514,328
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
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Takada, Saeko; Kwak, Seongae; Koppetsch, Birgit S et al. (2007) grp (chk1) replication-checkpoint mutations and DNA damage trigger a Chk2-dependent block at the Drosophila midblastula transition. Development 134:1737-44
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Theurkauf, W E; Hazelrigg, T I (1998) In vivo analyses of cytoplasmic transport and cytoskeletal organization during Drosophila oogenesis: characterization of a multi-step anterior localization pathway. Development 125:3655-66

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