Human cells have evolved protective mechanisms such as DNA repair and cell cycle checkpoints in order to promote stability of the genome. Studies on hereditary instability syndromes associated with a higher incidence of malignancies like Xeroderma pigmentosum or Nijmegen breakage syndrome demonstrated that genetic defects and subsequent dysfunction of a specific DNA repair mechanism trigger the development of cancer. Within the last years, the investigation of cell cycle checkpoints gained

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... asing importance in cancer research. Checkpoints are signaling cascades that halt the cell cycle in response to DNA damage, thereby providing time for repair and preventing accumulation of DNA alterations. While the p53-dependent G1-S checkpoint has been extensively investigated, little is known about other checkpoints in humans such as the G2-M or the S-phase progression checkpoint. Studies on the human cancer syndrome ataxia telangiectasia (AT) showed that AT cells fail to induce several checkpoints in response to ionizing radiation (IR), indicating that a checkpoint gene defect is responsible for the AT-associated cancers. The responsible gene (ATM) has significant sequence homology to the checkpoint kinase gene sprad3 in the fission yeast Schizosaccharomyces pombe (S. pombe). In S. pombe, spRad3 regulates G2-M checkpoint activation in response to DNA damage. Defects in the sprad3 gene, like defects in ATM, sensitize the organisms to radiation and radiomimetic drugs, suggesting conservation of checkpoint pathways from yeast to humans as well as a potential role of the G2-M checkpoint in carcinogenesis. The discovery of G2-M checkpoint-deficient yeast mutants led to the cloning of additional checkpoint genes in yeast and their human homologs. This group of novel human genes includes homologs of sprad9 (hRAD9), sphus1 (hHUS1), and sprad1 (hRAD1). In S. pombe, these genes are required for activation of spRad3, and defects in one or more of these genes render the yeast more sensitive to genotoxic agents. Mutations within th [...]