The Relationship Between p53 Gene and COVID-19
SARS-CoV-2 directly targets and suppresses p53 tumor suppressor function through viral protein interactions, which may increase cancer risk and reduce treatment efficacy in infected patients. 1, 2
Mechanisms of p53 Suppression by SARS-CoV-2
Direct Viral Interference
SARS-CoV-2 employs a "kidnap and exploit" strategy to circumvent p53 antiviral defenses, similar to oncogenic viruses like HPV and EBV. 1
The SARS nsp3 protein targets p53 for proteasomal degradation, actively reducing endogenous p53 levels in infected cells to facilitate viral replication. 1, 3
The viral spike protein (S2 subunit) disrupts the p53-MDM2 protein interaction, though direct binding between spike and p53 has not been definitively demonstrated in cellular studies. 2, 4
Functional Consequences on p53 Activity
SARS-CoV-2 spike protein suppresses p53 transcriptional activity, specifically inhibiting p53-mediated activation of critical genes including p21(WAF1), TRAIL Death Receptor DR5, and MDM2. 2
This suppression persists even after nutlin exposure (an MDM2 inhibitor that normally stabilizes p53), indicating robust viral interference with the p53 pathway. 2
Structural homology between SARS-CoV-2 and SARS-CoV-1 suggests the virus may directly impair both pRb and p53, which are key tumor suppressor gatekeepers. 5
Clinical Implications for Cancer Patients
Impact on Cancer Treatment Outcomes
Cisplatin-treated tumor cells expressing SARS-CoV-2 spike protein demonstrate increased cell viability compared to control cells, indicating reduced chemotherapy sensitivity. 2
Spike-expressing cells show altered γ-H2AX expression after cisplatin treatment, suggesting disrupted DNA damage sensing in the DNA damage response pathway. 2
Patients with cancer and COVID-19 experience higher mortality rates, with cancer being the main factor in 30-day mortality (24.4% vs 3.0% in general population, p < 0.001). 6
Potential Long-Term Carcinogenic Risk
Persistent SARS-CoV-2 infection may occur in some individuals, as evidenced by viral genomic material shedding weeks after apparent clinical resolution. 5
The combination of p53 impairment and marked oxidative stress from COVID-19's inflammatory response acts as both initiator and promoter of carcinogenesis. 5
Viral tropism toward immune-privileged territories may facilitate immune evasion, potentially enabling long-term viral persistence and cumulative DNA damage. 5
Therapeutic Considerations
p53 Restoration as Potential Treatment
SGT-53 (an investigational p53 gene therapy agent) represents a rational therapeutic approach for COVID-19, as it delivers exogenous wild-type p53 that functions as a pleiotropic transcription factor. 3
Restoring p53 function may counteract viral suppression of host immune responses, as p53 participates in both innate and adaptive immunity against viral infections. 3
This approach may have broader applicability to future viral pathogens that similarly manipulate p53-dependent pathways. 3
Critical Caveats
The interaction between SARS-CoV-2 proteins and p53 requires further validation in clinical samples, as most evidence derives from in vitro and in silico studies. 4
Cancer patients receiving cytotoxic therapy during or after COVID-19 infection may experience reduced treatment efficacy due to spike protein-mediated p53 suppression. 2
Long-term surveillance of COVID-19 survivors is warranted to monitor for potential increases in cancer incidence, though the magnitude of this risk remains undefined. 5
The effects of mRNA vaccines encoding spike protein on p53 function require investigation, particularly in cancer patients undergoing active treatment. 2