Radiation Checkpoints in Model Systems

Abstract

The response to DNA damaging agents includes a delay to progression through the cell cycle. Irradiation of premitotic cells causes a delay to mitosis and irradiation of G₁ and S phase cells causes a delay to DNA synthesis. These delays have become known as checkpoints. The mechanisms that mediate the mitotic (or G₂) checkpoint delay have recently come under study in yeast model systems. Work in the eukaryotic organisms S. cerevisiae and S. pombe has identified at least seven proteins controlling the interactions between DNA damage and cell cycle progression. Genetic analysis of this checkpoint pathway has identified substantial overlap with the feedback controls that co-ordinate progression through the cell cycle. Molecular analysis has revealed structural conservation between these highly diverged yeasts, which suggests that similar proteins may act in related pathways in mammalian cells. In addition, the rad24 and rad25 genes of S. pombe (which are involved in the radiation checkpoint) encode functionally overlapping essential proteins that are highly conserved in mammalian cells. Studies of checkpoints in the yeasts may therefore help to define the signal pathways that control cell cycle delay in mammalian cells following irradiation, some of which have been proposed to be deficient in A-T cells.