RETRACTED: SARS–CoV–2 Spike Impairs DNA Damage Repair and Inhibits V(D)J Recombination In Vitro

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS–CoV–2) has led to the coronavirus disease 2019 (COVID–19) pandemic, severely affecting public health and the global economy. Adaptive immunity plays a crucial role in fighting against SARS–CoV–2 infection and directly influences the clinical outcomes of patients. Clinical studies have indicated that patients with severe COVID–19 exhibit delayed and weak adaptive immune responses; however, the mechanism by which SARS–CoV–2 impedes adaptive immunity remains unclear. Here, by using an in vitro cell line, we report that the SARS–CoV–2 spike protein significantly inhibits DNA damage repair, which is required for effective V(D)J recombination in adaptive immunity. Mechanistically, we found that the spike protein localizes in the nucleus and inhibits DNA damage repair by impeding key DNA repair protein BRCA1 and 53BP1 recruitment to the damage site. Our findings reveal a potential molecular mechanism by which the spike protein might impede adaptive immunity and underscore the potential side effects of full-length spike-based vaccines.

Vaccination of elite athletes against SARS-CoV-2 and broader implications for public health policy

“…Furthermore, SARS--CoV--2 spike proteins delivered as components of inactivated--virus SARS--CoV--2 vaccines, possesses a near--zero probability of entering the nucleus of even a single cell, belonging to a recipient patient, while structurally intact. SARS--CoV--2 spike protein--mediated inhibition of DNA double--strand break repair mechanisms requires that an intact spike protein be localized to the nucleus (148). Conversely, vaccination of a population of elite strength, power and endurance athletes against SARS--CoV--2 with nucleotide vaccines exposes the athletes to clear and profound mechanistic risks of increased vaccination--induced adverse events.…”

“…Manifestations of the interactions of vaccine--induced, self--synthesized SARS--CoV--2 spike proteins and/or spike protein constituent components, such as S1, include, but are not limited to, pathological events such as thrombogenesis, endothelial dysfunction and myocarditis (154). Additionally, vaccine--induced, self-generated SARS--CoV--2 spike proteins may remain within the cell of origin and become localized to the nucleus, where inhibition of double stranded DNA repair mechanisms may occur (148). A temporal sequence can be described which characterizes the events which occur beginning with the administration of a SARS--CoV--2 nucleotide vaccine and ending with the generation of an antibody response of sufficient quality and/or quantity to neutralize the vaccine--induced, self-generated SARS--CoV--2 spike proteins and/or spike protein constituent components, such as S1.…”

“…(1.8) SARS-CoV-2 spike protein induced inhibition of DNA repair mechanisms SARS--CoV--2 spike proteins are capable of being localized to the nucleus in significant quantities, as isolated SARS--CoV--2 spike proteins have been detected within chromatin--bound cell fractions (148). Nuclearly localized, spike proteins have been reported to significantly impair double--strand DNA break (DSB) repair pathways, with reductions DSB repair activity reaching approximately 90% (148). Isolated SARS--CoV--2 spike proteins localized to the nucleus were found to directly inhibit the non--homologous end joining (NHEJ) repair pathway (148).…”

“…Nuclearly localized, spike proteins have been reported to significantly impair double--strand DNA break (DSB) repair pathways, with reductions DSB repair activity reaching approximately 90% (148). Isolated SARS--CoV--2 spike proteins localized to the nucleus were found to directly inhibit the non--homologous end joining (NHEJ) repair pathway (148). Isolated spike proteins localized to the nucleus were found to markedly inhibit the formation of 53BP1 foci, a key checkpoint protein for NHEJ repair (148).…”

Function and Molecular Mechanism of the DNA Damage Response in Immunity and Cancer Immunotherapy

“…Such knowledge is likely broadly applicable to human disease, including cancer, infectious disease and atherosclerotic disorders. For instance, SARS CoV-2 proteins, can hijack the human immune response to pathogens and the DNA damage repair system, thereby damaging both innate and adaptive immunity ( 295 , 296 ). Furthermore, the results of targeting endonuclease V, a ROS response and structure-specific nuclease that cleaves DNA and RNA at inosines as a regulator of innate immune responses, suggests blocking such DDR-related epitranscriptomic modifications to ameliorate carotid atherosclerosis and ischemic stroke ( 297 – 299 ).…”