RNA Viruses vs. DNA Synthesis: A General Viral Strategy That May Contribute to the Protective Antiviral Effects of Selenium

Abstract

The biosynthesis of DNA inherently competes with RNA synthesis because it depends on the reduction of ribonucleotides (RNA precursors) to 2’-deoxyribonucleotides by ribonucleotide reductase (RNR). Hence, RNA viruses can increase viral RNA production in cells by partially blocking the synthesis of DNA, e.g. by downregulating the mammalian selenoprotein thioredoxin reductase (TR), which normally acts to sustain DNA synthesis by regenerating reduced thioredoxin, a hydrogen donor for RNR. Computational and preliminary experimental evidence supports the hypothesis that a number of pathogenic RNA viruses, including HIV-1, Ebola, Zika, some flu viruses, and SARS-CoV-2, target TR isoforms by antisense. TR knockdown would create a host antioxidant defect that could be partially rectified by increased selenium intake, or be exacerbated by selenium deficiency, contributing to viral pathogenesis. There are several non-selenium-dependent means that viruses might also exploit to slow DNA synthesis, such as targeting RNR itself, or components of the glutaredoxin system, which serves as a backup redox system for RNR. HIV-1 substantially downregulates glutathione synthesis, so it interferes with both the thioredoxin and glutaredoxin systems. Computational results suggest that, like Ebola, SARS-CoV-2 targets TR3 by antisense. TR3 is the only TR isoform that includes an N-terminal glutaredoxin domain, so antisense knockdown of TR3 may also affect both redox systems, favoring RNA synthesis. In contrast, some DNA viruses encode their own glutaredoxins, thioredoxin-like proteins and even RNR homologues – so they are doing just the opposite, favoring DNA synthesis. This is clear evidence that viruses can benefit from shifting the RNA:DNA balance to their advantage.

SARS-CoV-2 suppresses mRNA expression of selenoproteins associated with ferroptosis, endoplasmic reticulum stress and DNA synthesis

“…According to computational analysis, SARS-CoV-2 targets TXNRD3 by antisense at several sites, with computed interaction energies equivalent to the strongest microRNA interactions. 18 Consistent with the computational prediction, our study found that SARS-CoV-2 significantly down-regulated TXNRD3, by 36.9% ( Figure 1E). TXNRD3 is mainly expressed in the testis.…”

“…Furthermore, the current work confirms the computational prediction that SARS-CoV-2 may boost virus production by downregulating TXNRD3. 18 These findings, summarized in Figure 2, provide a deeper insight into the connection between Se and SARS-CoV-2 and reinforce the potential importance of modulation of COVID-19 by Se.…”

“…Some large DNA viruses are equipped with their own ribonucleotide reductase to facilitate DNA synthesis for virus production. 18 Likewise, RNA viruses may attempt to suppress the diversion of ribonucleotides for DNA synthesis in order to enhance RNA synthesis. According to computational analysis, SARS-CoV-2 targets TXNRD3 by antisense at several sites, with computed interaction energies equivalent to the strongest microRNA interactions.…”

Understanding Selenium and Glutathione as Antiviral Factors in COVID-19: Does the Viral Mpro Protease Target Host Selenoproteins and Glutathione Synthesis?

“…These results are not unprecedented—our lab has shown that some RNA viruses target host mRNAs encoding isoforms of thioredoxin reductase via RNA:RNA antisense interactions, which, like proteolysis, would likely also result in host selenoprotein knockdown, but by a different mechanism ( 22 , 33 ). If our hypothesis is confirmed (i.e., some of these host cleavage sites prove to be functional), that leaves us with an interesting question—what evolutionary advantages are driving some viruses to go so far as to degrade or block the synthesis of GSH and specific host selenoproteins?…”

“…As a consequence of this basic fact of biochemistry, one should expect that RNA viruses might exploit various mechanisms to interfere with components of the thioredoxin and glutaredoxin systems, in order to minimize the diversion of ribonucleotides into DNA synthesis. This is simply the inverse of a strategy used by some large DNA viruses to maximize DNA production, by encoding their own thioredoxin-like proteins, glutaredoxins and even entire RNR genes ( 22 ). Consistent with this hypothesis, the results presented here suggest coronaviral targeting of TXNRD1, glutaredoxin-1, and GCLC, a key enzyme for GSH synthesis, for proteolytic cleavage.…”