6. Are the methylation strategies for cellular housekeeping generally omitted by vaccine mRNAs?
Methylation of mRNAs has been evolutionarily devised to control translation of transcripts and therefore expression of genes by a complex cascade of methylator (writers) and de-methylator (eraser) and reader proteins. A key methylation of adenosine “N6-methyladenosine (m6A)” in the 5′ UTR of mRNAs regulates normal cell physiology, the inflammatory response and cancer progression. The role and mechanisms of m6A in human disease is extensive and excellently covered in other comprehensive reviews [108,109]. Foremost among these, the SARS-CoV-2 molecular vaccination induces cell stress conditions, as is described by the elevated NF-κB signaling after vaccination [52,110].
Under conditions of cellular stress which can be induced by a viral infection or disease states such as cancer, m6A mediates mRNAs to undergo translation preferentially in a cap-independent way [111]. As discussed previously, this is opposite to the impact of mRNA SARS-CoV-2 vaccination, which drives cells toward a cap-dependenttranslation. Furthermore, under diversified conditions of cellular stress, there is an overwhelming induction of transcriptome-wide addition of m6A that causes an increased number of mRNAs to possess 5’UTRs enriched with m6A [111].
Eukaryotic translation initiation factor 4E (eIF4E) is the initial mRNA cap binding protein that directs ribosomes to the cap structure of mRNAs, in order to initiate translation into protein. The dependence on cap-dependent translation of vaccine mRNAs will consume a surplus of eIF4E availability needed to translate an unnaturally high number of synthetic mRNAs. However, the cap-independent translation takes place without requiring eIF4E to be bound to eIF4F. The competition for ribosomes will shift towards the cap-independent translation of transcripts, since the mRNAs undergoing cap-independent translation are equipped, apart from internal ribosome entry sites (IRES), with special binding motifs that bind to factors that actively recruit mRNAs to the ribosome cap-independent translational enhancers (CITEs) [112].
Furthermore, this also means that eIF4E, which is a powerful oncogene regulator and cell proliferation modulator, will sustain its activities by this competition, for an unnaturally prolonged period of time, trying to counterbalance the competition between robustly-capped mRNAs in vaccines and IRES-containing mRNAs [113,65]. This type of condition results in dysregulation of co-transcriptional m6A mRNA modifications and seriously links to molecular progressions of various cancers [114], as well as creating predisposing conditions for subsequent viral infections [113].
We next consider the impact of mRNA-vaccination-derived spike protein on the cellular IFN system via massive exosome production.