Isolation of Genes Required for the Regulated Separation of Sister Chromatids.
Annual rept. 1 Jun 98-31 May 99
SCRIPPS RESEARCH INST LA JOLLA CA
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Aneuploidy is a significant factor in the tumorogenic progression of breast cells. Failure in cell cycle checkpoint controls causes aneuploidy. Our goal has been to characterise checkpoint proteins required to maintain the fidelity of chromosome segregation. The anaphase inhibitor Pds1p is critically involved in this regulation. We identified a novel Pds1-dependent checkpoint pathway that prevents aneuploidy by coordinating DNA replication with mitotic anaphase. It is a distinct control system from the established S-phase checkpoint pathways previously described. A detailed characterisation of this checkpoint pathway is underway. Two more genes required for regulated chromosome segregation were identified, Rad23 and Ddi1. Structurefunction studies revealed a likely mechanism through which Rad23 and Ddi1 may regulate Pds1 by binding to ubiqutinated Pds1. Rad23 and Ddi1 contain a novel protein interaction domain UBA that binds to ubiquitin and ubiquitinated proteins. Rad23 and Ddi1 UBAs are essential for genetic interactions with a Pds1 mutant. These genes have closely related human homologues that are likely to be required for human checkpoint controls. Failure in such checkpoint mechanisms are a potential cause of aneuploidy that contributes to the etiology of breast cancer.
- Anatomy and Physiology
- Medicine and Medical Research