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The radiosensitization of tumor cells is one of the promising approaches for enhancing radiation damage to cancer cells and limiting radiation effects on normal tissue. In this study, we performed a comprehensive screening of radiosensitization targets in human lung cancer cell line A549 using an shRNA library and identified <i>apolipoprotein B mRNA editing enzyme catalytic subunit 3G</i> (<i>APOBEC3G: A3G</i>) as a candidate target. <i>APOBEC3G</i> is an innate restriction factor that inhibits HIV-1 infection as a cytidine deaminase. <i>APOBEC3G</i> knockdown with siRNA showed an increased radiosensitivity in several cancer cell lines, including pancreatic cancer MIAPaCa2 cells and lung cancer A549 cells. Cell cycle analysis revealed that <i>APOBEC3G</i> knockdown increased S-phase arrest in MIAPaCa2 and G2/M arrest in A549 cells after γ-irradiation. DNA double-strand break marker γH2AX level was increased in <i>APOBEC3G</i>-knocked-down MIAPaCa2 cells after γ-irradiation. Using a xenograft model of A549 in mice, enhanced radiosensitivity by a combination of X-ray irradiation and <i>APOBEC3G</i> knockdown was observed. These results suggest that the functional inhibition of <i>APOBEC3G</i> sensitizes cancer cells to radiation by attenuating the activation of the DNA repair pathway, suggesting that <i>APOBEC3G</i> could be useful as a target for the radiosensitization of cancer therapy.