REGULATION OF THE CELL-CYCLE FOLLOWING DNA-DAMAGE IN NORMAL AND ATAXIA-TELANGIECTASIA CELLS

A proportion of the population is exposed to acute doses of ionizing r adiation through medical treatment or occupational accidents, with lit tle knowledge of the immedate effects. At the cellular level, ionizing radiation leads to the activation of a genetic program which enables the cell to increase its chances of survival and to minimize detriment al manifestations of radiation damage. Cytotoxic stress due to ionizin g radiation causes genetic instability, alterations in the cell cycle, apoptosis, or necrosis. Alterations in the G1, S and G2 phases of the cell cycle coincide with improved survival and genome stability. The main cellular factors which are activated by DNA damage and interfere with the cell cycle controls are: p53, delaying the transition through the G1-S boundary; p21(WAF1/CIP1), preventing the entrance into S-pha se; proliferating cell nuclear antigen (PCNA) and replication protein A (RPA), blocking DNA replication; and the p53 variant protein p53as t ogether with the retinoblastoma protein (Rb), with less defined functi ons during the G2 phase of the cell cycle. By comparing a variety of r adioresistant cell lines derived from radiosensitive ataxia telangiect asia cells with the parental cells, some essential mechanisms that all ow cells to gain radioresistance have been identified. The results so far emphasise the importance of an adequate delay in the transition fr om G2 to M and the inhibition of DNA replication in the regulation of the cell cycle after exposure to ionizing radiation.