FAM122A is a housekeeping gene and highly conserved in mammals. More recently, we have demonstrated that FAM122A is essential for maintaining the growth of hepatocellular carcinoma cells, in which we unexpectedly found that FAM122A deletion increases γH2AX protein level, suggesting that FAM122A may participate in the regulation of DNA homeostasis or stability. In this study, we continued to investigate the potential role of FAM122A in DNA damage and/or repair. We found that CRISPR/Cas9-mediated FAM122A deletion enhances endogenous DNA damages in cancer cells but not in normal cells, demonstrating a significant increase in γH2AX protein and foci formation of γH2AX and 53BP1, as well as DNA breaks by comet assay. Further, we found that FAM122A deletion greatly increases TOP2α protein level, and significantly and specifically enhances TOP2 poisons (etoposide and doxorubicin)-induced DNA damage effects in cancer cells. Moreover, FAM122A is found to be interacted with TOP2α, instead of TOP2β. However, FAM122A knockout doesn’t affect the intracellular ROS levels and the process of DNA repair after removal of etoposide with short-term stimulation, suggesting that FAM122A deletion-enhanced DNA damage does not result from endogenous overproduction of ROS and/or impairment of DNA repair ability. Collectively, our study provides the first demonstration that FAM122A is critical for maintaining DNA stability probably by modulating TOP2α protein, and FAM122A deletion combined with TOP2-targeted drugs may represent a potential novel chemotherapeutic strategy for cancer patients.

FAM122A是管家基因，在哺乳动物中高度保守。最近，我们证明了FAM122A对于维持肝癌细胞的生长至关重要，我们意外地发现FAM122A缺失会增加γH2AX蛋白水平，这表明FAM122A可能参与了DNA稳态或稳定性的调节。在这项研究中，我们继续研究FAM122A在DNA损伤和/或修复中的潜在作用。我们发现CRISPR / Cas9介导的FAM122A缺失增强了癌细胞中的内源性DNA损伤，但未增强正常细胞中的内源性DNA损伤，这表明γH2AX蛋白的显着增加以及γH2AX和53BP1的病灶形成以及彗星试验的DNA断裂。此外，我们发现FAM122A缺失大大增加了TOP2α蛋白水平，并显着增强了TOP2毒物（依托泊苷和阿霉素）对癌细胞的DNA损伤作用。此外，发现FAM122A与TOP2α而不是TOP2β相互作用。但是，FAM122A敲除并不影响细胞内ROS的水平以及短期刺激下依托泊苷去除后DNA修复的过程，这表明FAM122A缺失增强的DNA损伤不是由内源性ROS过度产生和/或DNA损伤引起的修复能力。总的来说，我们的研究首次证明FAM122A对于维持DNA稳定性至关重要，可能是通过调节TOP2α蛋白来实现的，而FAM122A缺失与TOP2靶向药物的结合可能代表了癌症患者潜在的新型化疗策略。此外，发现FAM122A与TOP2α而不是TOP2β相互作用。但是，FAM122A敲除并不影响细胞内ROS的水平以及短期刺激下依托泊苷去除后DNA修复的过程，这表明FAM122A缺失增强的DNA损伤不是由内源性ROS过度产生和/或DNA损伤引起的修复能力。总的来说，我们的研究首次证明FAM122A对于维持DNA稳定性至关重要，可能是通过调节TOP2α蛋白来实现的，FAM122A缺失与TOP2靶向药物的组合可能代表了癌症患者潜在的新型化疗策略。此外，发现FAM122A与TOP2α而不是TOP2β相互作用。但是，FAM122A敲除并不影响细胞内ROS的水平以及短期刺激下依托泊苷去除后DNA修复的过程，这表明FAM122A缺失增强的DNA损伤不是由内源性ROS过度产生和/或DNA损伤引起的修复能力。总的来说，我们的研究首次证明FAM122A对于维持DNA稳定性至关重要，可能是通过调节TOP2α蛋白来实现的，而FAM122A缺失与TOP2靶向药物的结合可能代表了癌症患者潜在的新型化疗策略。FAM122A基因敲除不影响细胞内ROS水平以及短期刺激下依托泊苷去除后的DNA修复过程，这表明FAM122A缺失增强的DNA损伤不是由内源性ROS过度产生和/或DNA修复能力受损引起的。总的来说，我们的研究首次证明FAM122A对于维持DNA稳定性至关重要，可能是通过调节TOP2α蛋白来实现的，而FAM122A缺失与TOP2靶向药物的结合可能代表了癌症患者潜在的新型化疗策略。FAM122A基因敲除不影响细胞内ROS水平以及短期刺激下依托泊苷去除后的DNA修复过程，这表明FAM122A缺失增强的DNA损伤不是由内源性ROS过度产生和/或DNA修复能力受损引起的。总的来说，我们的研究首次证明FAM122A对于维持DNA稳定性至关重要，可能是通过调节TOP2α蛋白来实现的，而FAM122A缺失与TOP2靶向药物的结合可能代表了癌症患者潜在的新型化疗策略。