Friday Hope: Natural DNA Repair Pathway Therapeutics to Combat Spike-Induced DNA Damage Response

As we have been discovering, there are multiple uses for many natural compounds against SARS-CoV-2

Activation of DNA damage pathway in syncytia induced by SARS-CoV-2 infection and Spike-ACE2 expression. a and b Immunofluorescent images of Hela-ACE2 cells expressing exogenous SARS-CoV-2 spike glycoprotein (a) or infected by SARS-CoV-2 (b). Cells were stained with antibodies against γH2Ax protein in green. Zoomed images on the right indicate colocalization between γH2Ax and micronuclei in syncytia. Scale bars: 50 μm for the left image, 20 μm for zoomed images in the middle and 1 μm for multi-channel images on the right. c and d Quantification of micronuclei γH2Ax foci in Hela-ACE2 cells transfected by spike protein (c) or infected by SARS-CoV-2 (d). e–g Expression of γH2AX and p53 proteins in Hela-ACE2 cells 24 h post transfection by Western blot (e) and quantification (f, g). All results were normalized by the expression of β-actin. Data are mean ± SD of triple quantification. h Expression of NOXA, GADD45A, SLC7A11, PAI1 and MYC were analyzed by quantitative RT-PCR 24 h post spike transfection in Hela-ACE2 cells.

The above figure is from a paper which found that the Spike Protein is indeed inducing a high level of DNA damage response.

Here, we reported that viral infection could induce syncytia formation within cells expressing ACE2 and the SARS-CoV-2 spike protein, leading to the production of micronuclei with an average rate of about 4 per syncytium (> 93%). Remarkably, these micronuclei were manifested with a high level of activation of both DNA damage response and cGAS-STING signaling, as indicated by micronucleus translocation of γH2Ax and cGAS, and upregulation of their respective downstream target genes. Since activation of these signaling pathways were known to be associated with cellular catastrophe and aberrant immune activation, these findings help explain the pathological effects of SARS-CoV-2 infection at cellular and molecular levels, and provide novel potential targets for COVID-19 therapy.

Micronucleus production, activation of DNA damage response and cGAS-STING signaling in syncytia induced by SARS-CoV-2 infection
https://biologydirect.biomedcentral.com/articles/10.1186/s13062-021-00305-7#Abs1

However, what I DO NOT understand is why another paper showing how the Spike impairs DNA damage repair and impairs adaptive immunity. EVEN IF the contested conclusions about the Spike’s ability to impair adaptive immunity, the DNA damage repair impairment, I believe, was soundly shown.

Just because the full length Spike vaccine WAS NOT STUDIED DOES NOT INVALIDATE THE FINDINGS. I am BAFFLED (or am I, 😉) as to why this paper was retracted.

Adhering to our complaint procedure, an investigation was conducted. Both the chosen construct of the spike plasmid that contained a C-terminal fused with 6xHis tag and use of a GFP reporter system under overexpression conditions in the protocol were identified as having the potential to introduce significant ambiguity regarding the nature of the reported observations. The reliability of the results and conclusions presented have therefore been undermined. Furthermore, statements regarding the effect of the spike protein on the adaptive immunity are misleading as in this article no experiments related to the adaptive immunity were performed, and the full-length spike-based vaccine was not studied. Therefore, conclusions related to vaccine safety are not validated and lacked experimental support. This article is retracted and shall be marked accordingly. This retraction was approved by the Editor-in-Chief of the journal Viruses.

Retraction: Jiang, H.; Mei, Y.-F. SARS-CoV-2 Spike Impairs DNA Damage Repair and Inhibits V(D)J Recombination In Vitro. Viruses 2021, 13, 2056
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9145574/

Given that there have been multiple papers now about the Spike Protein’s ability to activate DNA damage repair mechanisms, it is clear that we need to find therapeutics to protect our DNA. What I find particularly fascinating is that the very same natural treatments that mitigate so much of what the Spike does, are also the very same treatments that help protect DNA. Berberine is one of these which I have not previously written about.

Once again, we find ASTOUNDING similarity between the effects of the SPIKE and the effects of CANCER. An interesting hypothesis I am pursuing is that the Spike Protein may be a transmissible “microtumor.” This would incorporate all my previous research and be a next step in our understanding of Spike Protein pathology if the hypothesis bears out.

Natural compounds are biologically active substances present in plants, fungi, bacteria, and other organisms that affect DNA repair, and are classified mainly according to their chemical structure into terpenes, carotenoids, phenolic compounds: phenolic acids, flavonoids, stilbenes, coumarins, tannins; alkaloids, nitrogen compounds; organosulfates: isothiocyanates and indoles, allyl sulfates. Flavonoids are further divided into chalcones, flavanones, flavones, flavonols, flavanols, isoflavones, and anthocyanins. In this work, we summarize the effects of different natural compounds on the DNA repair mechanisms of cancer cells and emphasize their possible application to re-sensitize these cells to radio and chemotherapy.

Let us look at a few highlights, starring some well-known players and some new ones.

RESVERATROL

As an anti-cancer compound, low-dose resveratrol accelerates non-mutagenic repair of DNA damage in mouse embryonic stem cells exposed to ionizing radiation. Similarly, resveratrol in mouse embryonic fibroblasts was shown to help maintain genomic stability after chemical and ionizing radiation damage by allowing greater repair efficiency of double-strand breaks and less replicative stress. Furthermore, resveratrol was shown to significantly reduce DNA damage from arsenic compounds in non-cancerous mammalian cells by enhancing repair activities, especially if used prior to exposure.

CURCUMIN

Furthermore, curcumin has shown multiple effects on DNA repair systems, both in healthy cells and cancer cells. Curcumin prevents DNA damage in lymphocytes of people chronically exposed to arsenic and improves its repair capacity. Thus, it induces an increase in the proteins of the base excision repair and non-homologous end joining pathways and collaborates to avoid carcinogenesis.

EGCG

Normal human leucocytes with continuous low-dose EGCG treatments show less DNA damage (single and double chain mutations, adducts, and mutations) when exposed to genotoxic agents such as bleomycin and some heterocyclic amines.

BERBERINE

Berberine is an isoquinoline alkaloid isolated mainly from the Chinese herb Coptis chinensis, although it is also present in other plants of the genus Berberis. It has a wide range of pharmacological properties such as anti-inflammatory, antibiotic, antitumor, antiarrhythmic functions, and it can regulate blood lipids and glucose levels. Berberine has been shown to induce oxidative DNA damage and alter RAD51 expression in ovarian cancer cells, breast cancer cells, and osteosarcoma cells, but not in normal cells, thereby causing increased DNA damage and longer, with abundant γH2AX, ATM, and p53 foci.

WITHANOLIDE D

Withanolide D, a compound obtained from Withania somnifera, was shown to improve the radiosensitivity of different cancer cell lines by inhibiting DNA damage via non-homologous end joining repair pathway.

Natural Compounds That Target DNA Repair Pathways and Their Therapeutic Potential to Counteract Cancer Cells
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710985/

Perhaps the most intriguing discovery I made working on this post, is that greatly INCREASING the dose of many of these compounds actually INDUCES DNA DAMAGE! This may be why there are so many conflicting studies on the effects of these compounds in treating Spike and SARS-CoV-2 related pathologies. The effective dose at an individual level may be difficult to determine. A dose that protects DNA for one individual may cause additional DNA damage in another.

As always, thank you for your support as we continue to elucidate the mechanisms of and treatments for the Spike Protein of SARS-CoV-2.