BRCA1 plays a critical role in homology-directed DNA repair (HDR), a process essential for maintaining genomic integrity. Mutations in BRCA1 lead to impaired HDR and increased nonhomologous end joining (NHEJ), resulting in genomic instability. This study demonstrates that Brca1-deficient mouse embryonic stem cells exhibit defective HDR of chromosomal DNA double-strand breaks (DSBs), with a significant reduction in gene targeting efficiency compared to wild-type cells. The defect in HDR is associated with a 53-fold decrease in gene targeting efficiency, while NHEJ is increased. These findings highlight BRCA1's role as a caretaker gene in preserving genomic stability by promoting HDR and limiting mutagenic NHEJ events. BRCA1 interacts with RAD51, a key protein in HDR, and is involved in DNA repair pathways. The study also shows that BRCA1-deficient cells have impaired HDR of DSBs, but are proficient in NHEJ. This suggests that BRCA1 is essential for HDR, and its loss leads to increased genomic instability. The results support the hypothesis that BRCA1 functions as a caretaker gene in maintaining genomic stability, with mutations leading to a high risk of breast and ovarian cancers.BRCA1 plays a critical role in homology-directed DNA repair (HDR), a process essential for maintaining genomic integrity. Mutations in BRCA1 lead to impaired HDR and increased nonhomologous end joining (NHEJ), resulting in genomic instability. This study demonstrates that Brca1-deficient mouse embryonic stem cells exhibit defective HDR of chromosomal DNA double-strand breaks (DSBs), with a significant reduction in gene targeting efficiency compared to wild-type cells. The defect in HDR is associated with a 53-fold decrease in gene targeting efficiency, while NHEJ is increased. These findings highlight BRCA1's role as a caretaker gene in preserving genomic stability by promoting HDR and limiting mutagenic NHEJ events. BRCA1 interacts with RAD51, a key protein in HDR, and is involved in DNA repair pathways. The study also shows that BRCA1-deficient cells have impaired HDR of DSBs, but are proficient in NHEJ. This suggests that BRCA1 is essential for HDR, and its loss leads to increased genomic instability. The results support the hypothesis that BRCA1 functions as a caretaker gene in maintaining genomic stability, with mutations leading to a high risk of breast and ovarian cancers.