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

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

Publication date: Jan 01, 2025

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.

Concepts Keywords
53bp1 ACE2 protein, human
Atm Angiotensin-Converting Enzyme 2
Host Angiotensin-Converting Enzyme 2
Kinases Animals
Virus ATM protein, human
ATR protein, human
Cell Fusion
cell fusion
Cell Line
Checkpoint Kinase 1
Checkpoint Kinase 1
Checkpoint Kinase 2
Checkpoint Kinase 2
CHEK1 protein, human
CHEK2 protein, human
Chlorocebus aethiops
COVID-19
DNA Damage
DNA damage response
Giant Cells
Humans
RAD51 protein, human
Rad51 Recombinase
Rad51 Recombinase
SARS-CoV-2
SARS‐CoV‐2
Signal Transduction
Spike Glycoprotein, Coronavirus
Spike Glycoprotein, Coronavirus
Spike protein
spike protein, SARS-CoV-2
Vero Cells

Semantics

Type Source Name
disease IDO role
disease IDO protein
disease MESH DNA damage
disease IDO host
disease IDO cell
disease MESH COVID-19
pathway REACTOME Signal Transduction

Original Article

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