CELLULAR RADIOSENSITIVITY IN ATAXIA-TELANGIECTASIA

Hypersensitivity to both the cell-killing and chromosome-damaging effe cts of ionizing radiations, and other agents causing DNA breakage, is a consistent feature of cells from individuals with the cancer-prone d isorder ataxia-telangiectasia (A-T). Evidence for a defect in DNA stra nd break rejoining is slight, but a higher-than-normal level of chromo somal breaks persists in irradiated A-T cells. There is also evidence for elevated frequencies of DNA recombination and deletion mutation in A-T cells; these responses may be linked through a loss of fidelity i n rejoining DNA breaks through recombination mechanisms. Additionally the regulation of cell-cycle responses is altered in A-T cells: in all phases of the cycle there is some loss of 'checkpoint' function short ly after irradiation, allowing cells to continue cycling despite exten sive DNA damage. However, on present evidence, radiation hypersensitiv ity cannot be explained simply by this loss of regulatory function. It is suggested that the A-T gene product acts in the early stages of a DNA damage-recognition pathway, normally interacting with regulatory p roteins such as p53, but also with proteins involved in the processing of DNA breaks. Reduced efficiency in this type of signalling function could well explain the link between radiosensitivity and cancer prone ness.