SARS-CoV-2 triggers DNA damage response in Vero E6 cells

Abstract

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus responsible for the current COVID-19 pandemic and has now infected more than 200 million people with more than 4 million deaths globally. Recent data suggest that symptoms and general malaise may continue long after the infection has ended in recovered patients, suggesting that SARS-CoV-2 infection has profound consequences in the host cells. Here we report that SARS-CoV-2 infection can trigger a DNA damage response (DDR) in African green monkey kidney cells (Vero E6). We observed a transcriptional upregulation of the Ataxia telangiectasia and Rad3 related protein (ATR) in infected cells. In addition, we observed enhanced phosphorylation of CHK1, a downstream effector of the ATR DNA damage response, as well as H2AX . Strikingly, SARS-CoV-2 infection lowered the expression of TRF2 shelterin-protein complex, and reduced telomere lengths in infected Vero E6 cells. Thus, our observations suggest SARS-CoV-2 may have pathological consequences to host cells beyond evoking an immunopathogenic immune response.

SARS-CoV-2 RNA elements share human sequence identity and upregulate hyaluronan via NamiRNA-enhancer network

“… 50 In accordance with DNA repair, the DNA damage response was triggered by SARS-CoV-2 in Vero E6 cells. 51 …”

Pulmonary infection by SARS-CoV-2 induces senescence accompanied by an inflammatory phenotype in severe COVID-19: possible implications for viral mutagenesis

“…Thus, an energy shift occurs resulting in increased ROS production, oxidative stress and DNA damage/DNA Damage Response (DDR) pathway activation. In addition, DDR and the subsequent cell cycle arrest may be driven by an interaction of Coronavirus nsp13 protein and DNA polymerase δ [ 54 ] and SASP via the cGAS/STING and other DNA damage dependent pathways ( Figure S8 ). Therefore, our previous work showing that DNA damage/DDR is a potent inducer of senescence, signifies its importance in the establishment of the viral induced senescence phenotype [ 31 ].…”

The potential role of COVID-19 in the induction of DNA damage

“…Concordantly, the ATR inhibitor berzosertib completely inhibits the replication of SARS-CoV, MERS-CoV and SARS-CoV-2 in epithelial cell lines, demonstrating that the replication of the novel coronavirus depends on ATR-dependent DNA-repair mechanisms [ 47 ]. Another recent study found that SARS-CoV-2 infection induces overexpression of ATR and CHK1 in viral host Vero E6 cells [ 48 ]. This effect was accompanied with increased phosphorylation levels of ATR, CHK1 and H2AX [ 48 ].…”

“…Another recent study found that SARS-CoV-2 infection induces overexpression of ATR and CHK1 in viral host Vero E6 cells [ 48 ]. This effect was accompanied with increased phosphorylation levels of ATR, CHK1 and H2AX [ 48 ]. At the genomic level, SARS-CoV-2 infection resulted in telomere shortening, which is a documented marker of cell senescence [ 48 ].…”

“…This effect was accompanied with increased phosphorylation levels of ATR, CHK1 and H2AX [ 48 ]. At the genomic level, SARS-CoV-2 infection resulted in telomere shortening, which is a documented marker of cell senescence [ 48 ]. Thus, demonstrating that replication fork stress and ATR deregulation are common mechanisms shared by coronaviruses, including SARS-CoV-2.…”