The events of the mitotic cell cycle are organized into dependent pathways in somatic cells and microorganisms: late events do not occur unless early events are completed. The RAD9 checkpoint, consisting of five gene products, assures the dependence of mitosis upon the completion of DNA replication. The RAD9 checkpoint increases the fidelity of the unperturbed mitotic cell cycle and maintains viability in the presence of intrinsic or extrinsic perturbations to DNA. We assume that the RAD9 pathway transduces a signal from incompletely replicated or damaged DNA to inhibit a component of the mitotic spindle, the target. In this project period we seek to: 1) Identify new checkpoints that we believe to be responsible for enforcing other dependent relationships in the mitotic cycle and for ensuring the high fidelity of mitotic chromosome transmission using the logic and methods developed in our study of the RAD9 pathway. 2) Order that RAD9 (and newly discovered checkpoint pathways) using dominant mutations and epistasis tests. 3) Elucidate the nature of the target of the RAD9 pathways) using dominant mutations and epistasis tests. 3) Elucidate the nature of the target of the RAD9 pathway (and other pathways) by isolating suppressors of the dominant mutations. 4) Identify a signal of the RAD9 pathway by locating the substrate of CDC13, a gene product that acts at a specific site near the end of the chromosome. 5) Elucidate the pathways of sister chromatid exchange which occur during cell cycle arrest at the RAD9 checkpoint. This work should increase our understanding of functions that insure the fidelity of the mitotic cell cycle and contribute to our insight into the origins of the cancer cell, a cell in which the loss of mitotic fidelity is likely to be causal in the disease.
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