DISRUPTION OF MOUSE RAD54 REDUCES IONIZING-RADIATION RESISTANCE

Double-strand DNA break (DSB) repair by homologous recombination occur s through the RAD52 pathway in Saccharomyces cerevisiae. Its biologica l importance is underscored by the conservation of many RAD52 pathway genes, including RAD54, from fungi to humans. We have analyzed the phe notype of mouse RAD54(-/)- (mRAD54(-/-)) cells. Consistent with a DSB repair defect, these cells are sensitive to ionizing radiation, mitomy cin C, and methyl methanesulfonate, but not to ultraviolet light. Gene targeting experiments demonstrate that homologous recombination in mR AD54(-/-) cells is reduced compared to wild-type cells. These results imply that, besides DNA end-joining mediated by DNA-dependent protein kinase, homologous recombination contributes to the repair of DSBs in mammalian cells. Furthermore, we show that mRAD54(-/-) mice are viable and exhibit apparently normal V(D)J and immunoglobulin class-switch r ecombination. Thus, mRAD54 is not required for the recombination proce sses that generate functional immunoglobulin and T cell receptor genes .