The study investigates the role of XRCC3 in homology-directed repair (HDR) of DNA double-strand breaks (DSBs) in mammalian cells. Using a novel fluorescence-based assay, the researchers found that XRCC3-deficient hamster cells exhibit a 25-fold reduction in HDR efficiency compared to wild-type cells. This defect can be restored by expressing XRCC3, but not other proteins involved in HDR. The results suggest that XRCC3 plays a crucial role in maintaining genomic integrity by promoting HDR, which is essential for preventing mutagenesis and lethality. The study also highlights the importance of XRCC3 in the repair of spontaneous DNA damage and its potential role in tumor suppression, as evidenced by the association of BRCA1 and BRCA2 with HDR processes.The study investigates the role of XRCC3 in homology-directed repair (HDR) of DNA double-strand breaks (DSBs) in mammalian cells. Using a novel fluorescence-based assay, the researchers found that XRCC3-deficient hamster cells exhibit a 25-fold reduction in HDR efficiency compared to wild-type cells. This defect can be restored by expressing XRCC3, but not other proteins involved in HDR. The results suggest that XRCC3 plays a crucial role in maintaining genomic integrity by promoting HDR, which is essential for preventing mutagenesis and lethality. The study also highlights the importance of XRCC3 in the repair of spontaneous DNA damage and its potential role in tumor suppression, as evidenced by the association of BRCA1 and BRCA2 with HDR processes.