FAM122A maintains DNA stability possibly through the regulation of topoisomerase IIα expression.

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 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 duanyu1670 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.

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