Role of damage-sensing/processing genes in the radiation response of haemopoietic in vitro colony-forming cells

Purpose: To characterize the role of various cellular damage-sensing, processing and survival genes in the in-vitro radiosensitivity of haemopoietic colony-forming cells. Materials and methods: Bone marrow cells from a range of different gene-knockout mice were irradiated in vitro with graded radiation doses and assayed for colony-forming efficiency. Results: Colony-forming efficiency in the nulls was often lower by up to threefold compared with the wild-types. This was noticeable in particular for the atm, bax and p21 nulls. Radiosensitivity was markedly increased in the scid mouse (about 2.3-fold), more than in the atm null mouse (about 1.7-fold). There was resistance in the p53 nulls compared with the wild-types, using two different background strains, that gave similar results. There was slight sensitization in the p21 nulls. In the bcl-2 nulls, there was sensitization at low dose, but not at high dose. In contrast, in the bax nulls, there was protection at low dose, but again not at high dose. The heterozygotes for p53, bcl-2 and bax responded similarly to the wild types, so that no gene dosage effects were identified. Conclusions: These studies are the first to elucidate the role of as many as six relevant genes in the radiosensitivity of a single cell type. They show the greater importance of 'survival' genes at lower cytotoxic doses of radiation compared with the greater importance of 'damage-sensing' genes at higher doses.