ATM/ATR-Mediated DNA Damage Response Facilitates SARS-CoV-2 Spike Protein-Induced Syncytium Formation

Multinucleated cells are present in lung tissues of patients infected by SARS-CoV-2. Although the spike protein can cause the fusion of infected cells and ACE2-expressing cells to form syncytia and induce damage, how host cell responses to this damage and the role of DNA damage response (DDR) signals in cell fusion are still unclear. Therefore, we investigated the effect of SARS-CoV-2 spike protein on the fusion of homologous and heterologous cells expressing ACE2 in vitro models, focusing on the protein levels of ATR and ATM, the major kinases responding to DNA damage, and their substrates CHK1 and CHK2. We found that both homologous and heterologous cell fusion activated the ATR-CHK1 and ATM-CHK2 signaling axis and induced the aggregation of γH2AX, 53BP1 and RAD51 in syncytia. In addition, siRNA or inhibitors of ATM and ATR suppressed syncytia formation by decreasing the level of S protein. These results showed the important role of DDR in stabilizing the S protein and in favoring its induction of cell fusion and syncytium formation, suggesting that the virus exploits the host DDR to facilitate its spread among infected cells.