Cell cycle-dependent repair of double-strand DNA breaks in a gamma-ray-sensitive Chinese hamster cell.

A Chinese hamster cell mutant has been isolated which is extremely sensitive to killing by gamma-irradiation in the G1 and early S phases of the cell cycle (LD50 of 20 vs. 250 rads for parent), but which has nearly normal resistance in late S. The mutant cell is able to repair single-stranded DNA breaks introduced by gamma-radiation. However, in comparison to its parental cell, the mutant is deficient in the repair of double-stranded DNA breaks produced by gamma-irradiation during the sensitive G1-early S period, while in the resistant late S period, the repair is nearly the same for both cell types. This correlation between gamma-ray sensitivity and repair strongly suggests that an inability to repair double-strand DNA breaks in G1 is the basis for the hypersensitivity of the mutant to killing by gamma-rays in this phase of the cell cycle. It also provides direct evidence in mammalian cells that the ability to repair double-strand DNA breaks induced by ionizing radiation is an important biochemical function in cell survival and supports the hypothesis that unrepaired double-strand breaks are a major lethal lesion in mammalian cells. A plausible explanation for the appearance of the cell cycle phenotype of the mutant is that in normal cells there are at least two pathways for the repair of double-strand breaks, one of which functions primarily in late S phase, and the other, either throughout the cell cycle or only in the G1 and early S phases.