Known and proposed interactions between SARS-CoV and SARS-CoV-2 and DNA damage response pathways

In a recent study published in Journal of Genetic Engineering and BiotechnologyResearchers reviewed the effects of infection with the severe acute respiratory syndrome coronavirus (SARS-CoV) on the host DNA damage response (DDR).

Background

Due to the small genome size of viruses, they utilize host cell mechanisms for replication. Therefore, the virus manipulates several cellular pathways, including DDR. DDR covers a number of signaling pathways that protect genomic integrity from extrinsic and endogenous DNA damage agents. Viral proteins can interact directly with DDR pathways that affect cell repair capacity. These interactions often lead to genomic instability associated with viral etiology.

One study found that nuclear imports of RNA-binding proteins were reduced during SARS-CoV-2 infection. The virus also manipulates the cell cycle for replication, affecting the host’s DNA replication and repair checkpoints. Although DDR manipulation by RNA viruses is important for their etiology, the underlying mechanism has not been fully studied. In the current review, researchers investigated the interaction of SARS-CoV-1 and SARS-CoV-2 with DDR proteins / pathways.

Interaction between SARS-CoV-1 protein and host protein

In one study, researchers identified the interaction between SARS-CoV-1 nonstructural protein (nsp) 13 and the host polymerase δ, which plays an important role in genomic replication. They showed an interaction between the p125 subunit of the polymerase and nsp13. nsp13 forms part of the viral replication and transcription complex and is crucial for viral replication.

The interaction between these proteins results in S phase arrest. The polymerase δ-nsp13 interaction causes a partial translocation of the polymerase to the cytoplasm, slowing the formation of delayed strands, resulting in single-strand breaks (SSBs) and ultimately replication. It has been proposed that it may be stopped.

These events lead to ataxic telangiectasia and Rad3-related (ATR) mobilization to stabilize a stopped replication fork. Given the 100% sequence similarity between the two SARS-CoV nsp13 proteins, this mechanism may be applicable to SARS-CoV-2 nsp13. In addition, recent studies have reported upregulation of ATR in SARS-CoV-2 infected VeroE6 cells. SARS-CoV-1 nsp3 was found to interact with human ring finger and CHY zinc finger domain-containing 1 (RCHY1) proteins.

Researchers have observed an increase in RCHY1-mediated degradation of the tumor suppressor p53. Targeted p53 degradation may enhance viral replication, as p53 acts as an antiviral factor that promotes the immune response and down-regulates viral replication. An interaction between the viral membrane (M) protein and phosphoinositide-dependent kinase 1 (PDPK1) has been discovered, but the effect of this interaction on cells remains unclear.

Interaction between SARS-CoV-2 and host protein

The SARS-CoV-2 envelope (E) protein interacted with the bromodomain protein (BRD). BRD is adopted during repair of double-strand breaks (DSBs). In addition to the interaction between the BRD and E proteins, one report showed that viral spike proteins enhance BRD4 expression, which regulates aging. As a result, increased DNA damage and cellular senescence were observed in infected cells. Treatment of cells with a BRD4 inhibitor reversed the aging phenotype.

The interaction of virus ORF8 with host DNA methyltransferase 1 (DNMT1) was identified. Studies with hepatitis C virus (HCV) have shown that the virus utilizes DNMT1 and DNMT3B for proliferation because subgenome replication of HCV is inhibited by the downregulation of either methyltransferase. Therefore, the authors believe that the SARS-CoV-2 ORF8-host DNMT1 interaction may affect the host DNA repair process. However, more research is needed to investigate whether DNMT1 inhibitors affect the pathogenicity of SARS-CoV-2.

SARS-CoV-2 nsp1 is the key to regulating viral replication and enhances infectivity by downregulating the host’s antiviral pathways. nsp1 has been demonstrated to interact with all subunits of DNA polymerase α. Since polymerases are essential for the initiation of DNA replication and non-homologous end binding (NHEJ), the authors suggested that the interaction of nsp1-polymerase α may cause replication stress and defects in NHEJ.

One study identified an interaction between histone deacetylase 2 (HDAC2) and the virus nsp5. nsp5 is predicted to process the cleavage site between the nuclear localization sequence of HDAC2 and the catalytic domain. Therefore, it has been proposed that nsp5-HDAC2 interactions may interfere with the nuclear localization of deacetylase and the subsequent activation of the interferon response pathway.

Conclusion

Multiple SARS-CoV-2 proteins have been reported to interact with a variety of DDR-related host proteins and may adversely affect their contribution to DNA damage repair. The authors reviewed the interaction of SARS-CoV proteins with DDR and suggested some possible effects of DNA repair and genomic stability.

Promising results have been observed with drugs targeting DDR for antiviral activity. Berzosertib, an ATR kinase inhibitor, not only inhibits SARS-CoV-1 replication, but also exhibits potential anti-SARS-CoV-2 activity in various cell lines. Most DDR and SARS-CoV-2 protein interactions have been discovered by in silico or high-throughput approaches. Therefore, future research needs to ly validate the potential use of these DDR proteins as drug discovery targets.