DNA double-strand breaks are potentially hazardous lesions that can be induced by ionizing radiation, radiomimetic chemicals, or DNA replication inhibitors. Cells recognize and repair DSBs via two distinct but partly overlapping signaling pathways: non-homologous end joining and homologous recombination. DNA repair via the HR pathway is restricted to S and G2 phases of the cell cycle, while NHEJ can occur during any phase. NHEJ machinery is also utilized in V(D)J recombination, a process that generates diversity in immunoglobulin and T cell receptor genes. Defects in both pathways have been associated with human disease, including cancer.DNA repair through the NHEJ pathway involves a core group of proteins that includes the Ku heterodimer, DNA-PKcs, DNA ligase IV, X-ray repair cross-complementing protein 4, XLF, and PAXX. XRCC4 interacts with XLF and promotes the ligation of DNA strands by DNA ligase IV.Mutations and polymorphisms in XRCC4 have been linked to human disease, including microcephaly, dwarfism, and cancer susceptibility. Knockdown of XRCC4 expression in hepatocellular carcinoma cells and triple-negative breast cancer cells increases sensitivity to doxorubicin and ionizing radiation, respectively.
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