Abstract
Genetic instability is considered to be a major driving force of malignancy of cancer cells, and at least some of cancer-associated genetic instability is known to be caused by defects in the cell cycle checkpoint control. Patients of the cancer-prone genetic disorder ataxia telangiectagia frequently develop malignant lymphoma and their cells are defective in γ-irradiation responsive checkpoint control, whereas cells inactivated for the p53 recessive oncoprotein are defective in DNA damage-induced checkpoint control and develop genetic instability. Cells contain two major cell cycle checkpoint control systems: DNA-replication checkpoint, DNA-damage checkpoint. These checkpoint systems are thought to consist of three functionally distinct components: sensors, checkpoint signal transducers and cell cycle effecters. Recent rapid progress in the identification of these components is beginning to prove this conceptual model and the generality of the checkpoint system among eukaryotes. The full understanding of the cell cycle checkpoint control system will provide deeper insights into the highly complex mechanisms of carcinogenesis and highlight possible targets for cancer therapy.
Highlights
One of the key properties of malignantly transformed cells is genetic instability
Recent advances in cell cycle research indicate that a defect in a checkpoint control may be responsible for the genetic instability of at least some cancer cells (Hartwell and Kastan, 1994)
The p53 recessive oncogene, which is inactivated in a variety of cancer cells, is required for genetic stability and γ-irradiation induced G1 checkpoint arrest (Ko and Prives, 1996; Sherr, 1996), whereas ataxia telangiectasia mutated gene product (ATM), the causative gene for cancerprone ataxia telangiectasia, structurally resembles a checkpoint gene in yeast and is essential for γirradiation induced checkpoint arrest (Savitsky et al, 1995; Elledge, 1996; Sherr, 1996)
Summary
One of the key properties of malignantly transformed cells is genetic instability. Genetic instability itself, has no contribution to malignant phenotypes but is considered to act as a powerful engine driving activation and inactivation of a variety of oncogenes and recessive oncogenes, which lead to the expression of malignant phenotypes. Fission yeast cells deleted for a component of ORC (Muzi-Falconi and Kelly, 1995; Grallert and Nurse, 1996; Leatherwood et al, 1996), Cdc7-related kinase (Masai et al, 1995), a MCM homologue (Maiorano et al, 1996), or Cdc18 (Kelly et al, 1993) enter mitosis without DNA synthesis, indicating that the pre-replication complex is likely to be a major object detected by a checkpoint sensor.
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