The Roles of N 6 -Methyladenosine in Human Diseases

Abstract

N ⁶-Methyladenosine methylations and demethylations are associated with a number of human diseases. A chemical and biochemical perspective can complement the biological view of the epigenetic mechanism. The orbital of imino nitrogen and nitrogen-hydrogen orbital displays p-π conjugation and σ-σ hyperconjugation. The electron delocalization attenuates secondary chemical bonding, resulting in low affinities on the imino nitrogen atom to cations. Reduced proton accumulation via N ⁶-methyladenosine correlates to lower cellular proton levels which may reflect cell physiology and pathogenesis. The lower affinity of the imino nitrogen to divalent cations in the methylated form versus the nonmethylated form may lead to reduced formation of insoluble and rigid calcium oxalate, which was proposed to be the cause of many diseases. The chemical and biochemical attributes of N⁶-methyladenosine crosstalk with biological pathways upregulating and/or downregulating gene expressions to give rise to various physiological and biochemical outcomes at the cellular levels and the organismal levels.

N⁶-Methyladenosine (m⁶A) is an abundant modification found in messenger RNA (mRNA), transfer RNA (tRNA), ribosomal RNA (rRNA), and small nuclear RNA (snRNA) as well as some long noncoding RNA. m⁶A elicits a number of biological functions, eg, acceleration of the processing of mRNA precursors. ¹ Although the biological mechanism for m⁶A methylation is demonstrated, ² the functional role of the methylation itself in m6A remains elusive. Overexpression or downregulated expression of m⁶A writers are both associated with tumor cell growth, proliferation, and so on, as they may upregulate or downregulate the expression of oncogenes and tumor suppressors. ³ The downregulated expression of m⁶A erasers is mostly linked to proliferation and invasiveness of cancer cells. ³ The associations between m⁶A demethylation and several cancer types have been demonstrated.^4-7 The link between m⁶A and neuronal disorders has also been described. ⁷ The p orbital of imino nitrogen and adjacent π orbital display p-π conjugation and the σ orbital of -NH- and the σ orbital of carbon-hydrogen in attached methyl group display σ-σ hyperconjugation (Figure 1). The electron delocalization reduces C-N bond lengths and weakens secondary chemical bonding, and gives rise to low affinities on the imino nitrogen atom to cations. Reduced proton buildup via m⁶A correlates to lower cellular proton levels and perhaps lower cancer risks evident in associations between m⁶A erasers and several cancer types, as HCl may be implicated in carcinogenesis.^8,9 Calcium supplement can neutralize strong acids and substantially reduce cancer risks. ⁸ Red meat is modestly carcinogenic as defined by World Health Organization and is characterized by the presence of myoglobin whose basic amino acid content is around 21%, attracting anions such as Cl⁻ and contributing to the formation of HCl. ⁸ The noncoastal Chinese southern Yunnan Province registered low nasopharyngeal cancer incidences, whereas the coastal south China and humid Southeast Asia are prevalent in nasopharyngeal carcinoma, ¹⁰ suggesting that hydrogen bonding to protons is critical for carcinogenesis. The lower affinity of the imino nitrogen to calcium leads to reduced formation of insoluble and rigid calcium oxalate in the methylated form in comparison with the nonmethylated form, and calcium oxalate was proposed to be a major cause of neurodegenerative disorders and cardiovascular diseases. ¹¹ With structure similar to oxalate, alcohol and acetic acid can treat heart disease and extend lifespan, perhaps via the inhibition of oxalate generation. ¹² Glycolic acid has been used in skincare products to reduce age-related wrinkles, possibly through the aforementioned mechanism. In summary, a chemical and biochemical perspective sheds light on the epigenetic mechanism of m⁶A molecule itself with methylations and demethylations, in addition to the understandings of the biological networks executing the modifications and regulating the processes. This will further our knowledge on the roles played by DNA and RNA methylations.

Figure 1.

Chemical and biochemical perspective on the epigenetic mechanism of N ⁶-methyladenosine.