Adenosine methylation as a molecular imprint defining the fate of RNA

Abstract

Multiple lines of evidence suggest the RNA modification N 6‐methyladonsine (m6A), which is installed in the nucleus cotranscriptionally and, thereafter, serves as a reversible chemical imprint that influences several steps of mRNA metabolism. This includes but is not limited to RNA folding, splicing, stability, transport and translation. In this Review we focus on the current view of the nuclear installation of m6A as well as the molecular players involved, the so called m6A writers. We also explore the effector proteins, or m6A readers, that decode the imprint in different cellular contexts and compartments, and ultimately, the way the modification influences the lifecycle of an RNA molecule. The wide evolutionary conservation of m6A and its critical role in physiology and disease warrants further studies into this burgeoning and exciting field.

N6-Methyladenosine Role in Cancer: Learning from AML

“…In mammalian cells, about 0.4% of adenosines inside mRNAs are m 6 A modified (1-5 m 6 A sites per transcript) [4,5]. m 6 A modifications into mRNAs are catalysed by a heterodimeric core complex comprised of methyltransferase-like protein 3 (METTL3) and methyltransferase-like protein 14 (METTL14), which specifically methylates the adenosine within the DRACH motif (where D =A/G/U, R=A/G; H=A/C/U).…”

“…The m 6 A modification is installed by "writers" and removed by "erasers", in addition, it can recruit specific "reader" proteins. m 6 A modification and the associated regulatory proteins play a critical role in gene expression by affecting different steps of the mRNA life, including splicing, nuclear export, stability and translation [4,5]. The reversible and dynamic nature of m 6 A modification and its ability to fine-tune and coordinate gene expression programs has attracted the interest of many research groups in order to define its contribution to cell differentiation, normal development and human diseases [4].…”

Deciphering the ‘m6A code’ via quantitative profiling of m6A at single-nucleotide resolution

“…Six years ago, we and others developed immunoprecipitation-based approaches coupled with high-throughput sequencing (m6A-seq, m6A-MeRIP), allowing to detect regions harboring m6A ('m6A peaks') (Dominissini et al, 2012;Meyer et al, 2012) . These approaches paved the way to major advances in the understanding of m6A, its distribution and conservation, and have facilitated the functional and mechanistic dissection of m6A in development and disease (reviewed in (Knuckles and Bühler, 2018;Meyer and Jaffrey, 2017;Schwartz, 2016;Yue et al, 2015) ).…”

Cross-talk between m6A and m1A regulators, YTHDF2 and ALKBH3 fine-tunes mRNA expression

“…A large number of studies in the last 6 years have convincingly proven the impact of N 6 -methyl adenosine (m6A) -the most abundant modification on eukaryotic mRNA -on all aspects of RNA metabolism including spicing, stability, translation, microRNA processing (1)(2)(3)(4)(5)(6)(7) and several physiological processes including cancer, immunity and memory (8)(9)(10). The reversible m6A modification is installed by the m6A writer complex (11) containing the catalytic core METTL3 and METTL14 proteins (12) and removed by the m6A erasers ALKBH5 and FTO (13,14). The m6A readers bind m6A RNA targets to mediate their fate.…”