Exposure of human cells of ionizing radiation leads to growth delays mediated by arrests in the progression of cells through different phases of the cell cycle. It is believed that they serve as checkpoints where the integrity of the genome is assessed before allowing further progression through the cycle. It is further assumed that the time of arrest is exploited by the cell to process unrepaired radiation damage. One could therefore, in principle, control the level if repair carried out in irradiated cells by modulating the duration of radiation-induced delays. We hypothesize that prolongation of the duration of radiation-induced G2 delay will promote repair in irradiated cells and will reduce the lethal and mutagenic effects of radiation.

The proposed research is funded on the novel observation that cells excrete into the growth medium a low molecular weight factor(s), most likely a peptide, with G2 arrest modulating activity (GAMA), that dramatically increases the duration of G2 arrest. We will establish the molecular nature and primary structure of GAMA and will proceed with the preparation of monoclonal and polyclonal antibody reagents. We will study the effect of GAMA on cell lethality and mutation induction, and will determine whether the peptide is derived from a precursor protein. We will synthesize GAMA and will compare the activity of receptors for GAMA and clone the genes for the precursor protein (if any) and the receptor.

We speculate that characterization of GAMA will define a novel group of compounds which modulate G2 arrest and thus, probably also radiosensitivity and mutagenicity. Such compounds may be useful radioprotectors, acting via modulation repair pathways, as opposed to the radical scavenging properties of classical radioprotectors. They may be beneficial individuals even when administered after exposure to ionizing radiation, because the repair process they modulate require hours for completion whereas radicals decay within msec.