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.