The dynamic N1-methyladenosine methylome in eukaryotic messenger RNA

Abstract

Gene expression can be regulated post-transcriptionally through dynamic and reversible RNA modifications. A recent noteworthy example is N6-methyladenosine (m6A), which affects messenger RNA (mRNA) localization, stability, translation and splicing. Here we report on a new mRNA modification, N1-methyladenosine (m1A), that occurs on thousands of different gene transcripts in eukaryotic cells, from yeast to mammals, at an estimated average transcript stoichiometry of 20% in humans. Employing newly developed sequencing approaches, we show that m1A is enriched around the start codon upstream of the first splice site: it preferentially decorates more structured regions around canonical and alternative translation initiation sites, is dynamic in response to physiological conditions, and correlates positively with protein production. These unique features are highly conserved in mouse and human cells, strongly indicating a functional role for m1A in promoting translation of methylated mRNA.

ALKBH1-Mediated tRNA Demethylation Regulates Translation

“…This methylation is known to be critical to the stability of tRNA iMet (Anderson et al, 1998). m 1 A has recently been discovered as another mRNA modification, in addition to m 6 A, pseudouridine, and m 5 C. The presence of m 1 A at the 5′ UTR region in mRNA has been suggested to promote translation (Dominissini et al, 2016;Li et al, 2016). ALKBH3, a DNA repair enzyme that demethylates N 1 -methyldeoxyadenosine in single-stranded DNA (Aas et al, 2003;Duncan et al, 2002) has been suggested as a potential demethylase of m 1 A in mRNA , the functional relevance of which still requires further investigations.…”

“…For instance, the m 6 A reader protein YTHDF1 specifically associates with the m 6 A sites and promotes translation by interacting with the translation initiation complex (Wang et al, 2015). The recently identified mRNA modification m 1 A in mRNA is suggested to be related to active translation as well (Dominissini et al, 2016;Li et al, 2016), although the m 1 A-binding protein and the underlying mechanism have yet to be unveiled. tRNA modifications have long been thought to affect translation by fine-tuning tRNA structures and their interactions with the corresponding mRNA codons (Agris, 2008;Agris et al, 2007).…”

NSUN 3 and ABH 1 modify the wobble position of mt‐t RNA Met to expand codon recognition in mitochondrial translation

“…Several modified ribonucleosides including 6‐methyladenosine (m 6 A), 5‐methylcytidine (m 5 C), 1‐methyladenosine (m 1 A) and pseudouridine have recently been shown to occur in messenger (m)RNAs and to affect their biogenesis, translation and stability (see e.g. Carlile et al , 2014; Liu & Jia, 2014; Dominissini et al , 2016). Methylated nucleosides can undergo further modification and proteins of the AlkB family of alpha‐ketoglutarate and Fe(II)‐dependent dioxygenases (ALKBH1‐8 and FTO in human cells) can oxidise or even remove modifications in DNA and RNA (Fedeles et al , 2015; Ougland et al , 2015), increasing the dynamics and regulation of RNA modifications and their roles in RNA metabolism.…”

Profiling of m6A RNA modifications identified an age‐associated regulation of AGO2 mRNA stability

“…Methylation profiles have revealed differential patterns of RNA modification, for instance, the pattern of m1A's are nearby translation start codons and first splice sites, and m6A sites are primarily within the 3' UTR (Dominissini et al., 2012, 2016). Recently, a study observed NAD + ‐modified RNA has been observed in yeast and mammals, and their results implied a function in mRNA translation and decay (Jiao et al., 2017; Walters et al., 2016).…”