This study investigates the role of histone H2AX in genomic stability in mice. H2AX is a histone variant that becomes phosphorylated at the site of double-strand breaks (DSBs), facilitating the recruitment of DNA repair factors. The researchers generated H2AX-deficient mice and observed that these mice were radiation-sensitive, growth-retarded, immune-deficient, and infertile. These phenotypes were associated with chromosomal instability, repair defects, and impaired recruitment of Nbs1, 53bp1, and Brca1 to DSBs, but not Rad51. H2AX is critical for the assembly of specific DNA repair complexes on damaged DNA. H2AX is not essential for irradiation-induced cell-cycle checkpoints, as evidenced by the normal phosphorylation of Nbs1 in H2AX-deficient mice. However, H2AX-deficient mice showed increased chromosomal abnormalities, including a higher frequency of chromatid breaks and dicentric chromosomes, and a significant increase in chromosomal translocations and rearrangements. These findings suggest that H2AX deficiency leads to genomic instability. H2AX-deficient mice also exhibited impaired DNA repair, as evidenced by increased DNA fragmentation and reduced DNA repair efficiency after irradiation. This deficiency in DNA repair may contribute to the radiation hypersensitivity of H2AX-deficient mice. Additionally, H2AX-deficient mice showed impaired immunoglobulin class-switch recombination, with reduced levels of IgG3 and impaired antibody responses to antigens. H2AX is required for efficient homologous recombination (HR), as evidenced by reduced homologous integration in H2AX-deficient embryonic stem cells. H2AX is also essential for the formation of irradiation-induced Nbs1, 53bp1, and Brca1 foci, but not for the assembly of Rad51 foci. H2AX is required for the proper formation of meiotic structures, as evidenced by defects in spermatogenesis and impaired sex-chromosome segregation in H2AX-deficient mice. Overall, this study demonstrates that H2AX is critical for maintaining genomic stability and facilitating DNA repair. H2AX deficiency leads to chromosomal instability, impaired DNA repair, and defects in meiotic processes, highlighting the importance of H2AX in maintaining genomic integrity.This study investigates the role of histone H2AX in genomic stability in mice. H2AX is a histone variant that becomes phosphorylated at the site of double-strand breaks (DSBs), facilitating the recruitment of DNA repair factors. The researchers generated H2AX-deficient mice and observed that these mice were radiation-sensitive, growth-retarded, immune-deficient, and infertile. These phenotypes were associated with chromosomal instability, repair defects, and impaired recruitment of Nbs1, 53bp1, and Brca1 to DSBs, but not Rad51. H2AX is critical for the assembly of specific DNA repair complexes on damaged DNA. H2AX is not essential for irradiation-induced cell-cycle checkpoints, as evidenced by the normal phosphorylation of Nbs1 in H2AX-deficient mice. However, H2AX-deficient mice showed increased chromosomal abnormalities, including a higher frequency of chromatid breaks and dicentric chromosomes, and a significant increase in chromosomal translocations and rearrangements. These findings suggest that H2AX deficiency leads to genomic instability. H2AX-deficient mice also exhibited impaired DNA repair, as evidenced by increased DNA fragmentation and reduced DNA repair efficiency after irradiation. This deficiency in DNA repair may contribute to the radiation hypersensitivity of H2AX-deficient mice. Additionally, H2AX-deficient mice showed impaired immunoglobulin class-switch recombination, with reduced levels of IgG3 and impaired antibody responses to antigens. H2AX is required for efficient homologous recombination (HR), as evidenced by reduced homologous integration in H2AX-deficient embryonic stem cells. H2AX is also essential for the formation of irradiation-induced Nbs1, 53bp1, and Brca1 foci, but not for the assembly of Rad51 foci. H2AX is required for the proper formation of meiotic structures, as evidenced by defects in spermatogenesis and impaired sex-chromosome segregation in H2AX-deficient mice. Overall, this study demonstrates that H2AX is critical for maintaining genomic stability and facilitating DNA repair. H2AX deficiency leads to chromosomal instability, impaired DNA repair, and defects in meiotic processes, highlighting the importance of H2AX in maintaining genomic integrity.