The RAD52 epistasis group is required for recombinational repair of double-strand breaks (DSBs) and shows strong evolutionary conservation. In Saccharomyces cerevisiae, RAD52 is one of the key members in this pathway. Strains with mutations in this gene show strong hypersensitivity to DNA-damaging agents and defects in recombination. Inactivation of the mouse homologue of RAD52 in embryonic stem (ES) cells resulted in a reduced frequency of homologous recombination. Unlike the yeast Scrad52 mutant, MmRAD52 ؊/؊ ES cells were not hypersensitive to agents that induce DSBs. MmRAD52 null mutant mice showed no abnormalities in viability, fertility, and the immune system. These results show that, as in S. cerevisiae, MmRAD52 is involved in recombination, although the repair of DNA damage is not affected upon inactivation, indicating that MmRAD52 may be involved in certain types of DSB repair processes and not in others. The effect of inactivating MmRAD52 suggests the presence of genes functionally related to MmRAD52, which can partly compensate for the absence of MmRad52 protein.Double-strand breaks (DSBs) in the DNA of living organisms occur during several physiological processes including meiotic recombination, mating-type switching in yeast, and V(D)J rearrangement in developing B and T lymphocytes. Agents such as ionizing radiation and certain chemicals also lead to the induction of DSBs in the genome. If left unrepaired, DSBs result in broken chromosomes and cell death, as has been shown convincingly in yeast (5). Alternatively, incorrect repair of DSBs may generate deletions, chromosome rearrangements, and cell transformation and eventually lead to the formation of tumors.Two main pathways are known to be involved in the repair of DSBs in eukaryotes: end-to-end rejoining, a homology-independent but error-prone process, and error-free repair via (homologous) recombination. Repair of DSBs in the yeast Saccharomyces cerevisiae occurs predominantly via recombination, whereas a contribution of end-to-end rejoining can be observed only in a recombination-deficient background (9, 27, 47). Recombinational repair in S. cerevisiae involves the genes of the RAD52 epistasis group, of which nine members have been identified thus far (ScRAD50, ScRAD51, ScRAD52, ScRAD54, ScRAD55, ScRAD57, ScRAD59, ScMRE11, and ScXRS2) (2,11,15,16,44). Interestingly, it has been shown that ScRAD50, ScMRE11, and ScXRS2 are also involved in end-to-end rejoining (10,28,55). Mutations in genes of the RAD52 group result in an increased sensitivity to ionizing radiation and defects in one or more types of recombination. Among these mutants, the Scrad51, Scrad52, and Scrad54 mutants display the most severe radiation sensitivity and defects in recombination.Biochemical experiments with S. cerevisiae have shown that the ScRad51 protein forms nucleoprotein filaments with single-stranded DNA and promotes pairing and limited strand exchange (51). The ScRad52 protein alone or a heterodimer of ScRad55 and ScRad57 functions as a cofactor in this reaction, ...