Genomic instability, the hallmark of human cancer, can involve activating mutations at oncogene loci, the accumulation of tumor suppressor mutations and specific chromosome losses that uncover tumor suppressor deficiencies. Cell cycle checkpoint, roritriols guard against such genome alterations. Indeed, high fidelity chromosome replication and transmission depend on elaborate mechanics that must be precisely controlled in the cell cycle context The S-phase checkpoint is a mechanism that establishes a dependence relationship between the biochemically unrelated cellular processes of DNA replication and mitotic cell division. A functional S-phase checkpoint ensures that genome duplication and segregation occur without error and this checkpoint is therefore a critical signaling pathway that guards against genome instability. Understanding S-phase checkpoint control is an important goal to increase our knowledge of cancer etiology. In the clinic, checkpoint integrity of tumor cells is highly relevant for designing effective treatment regimes, since compromised checkpoint controls affect the sensitivity of cells to therapeutic agents. This application seeks to understand the functions of novel S-phase checkpoint components. In addition, we propose to specifically investigate a novel Late S-phase Checkpoint pathway that we recently identified. Some, but not all, of the late S-phase checkpoint components are known. We will therefore investigate the functions of known S-phase checkpoint proteins and screen for currently unknown factors. These factors will inevitably be critical for the maintenance of genome stability and will be conserved in humans.
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