Abstract
Simple SummaryThe m6A is the most abundant and well-studied modification of mRNA, and plays an important role in transcription and translation. It is known to be evolutionarily conserved machinery present in the last eukaryotic common ancestor (LECA). The writers and erasers responsible for adding or removing m6A belong to specific protein families, respectively, suggesting that these members are evolutionarily related. However, only some of these mRNA m6A modification-associated proteins have been studied from an evolutionary perspective, while there has been no comprehensive and systematic analysis of the distributions and evolutionary history of N6mA-associated proteins in the three kingdoms of life. In this study, we identified orthologues of all the reported N6mA-associated proteins in 88 organisms from three kingdoms of life and comprehensively reconstructed the evolutionary history of the RNA N6mA modification machinery. The results demonstrate that RNA N6mA-MTases are derived from at least two different types of prokaryotic DNA MTases (class α and β MTases). As the m6A reader, YTH proteins may be acquired by LECA from an individual prokaryotic YTH-domain protein that evolved from the N-terminals of an R-M system endonuclease. In addition, the origin of eukaryotic ALKBH family proteins is inferred to be driven by at least two occasions of independent HTG from the bacterial ALKB family.Methylation at the N6-position of adenosine (N6mA) on mRNA (m6A) is one of the most widespread, highly selective and dynamically regulated RNA modifications and plays an important role in transcription and translation. In the present study, a comprehensive analysis of phylogenetic relationships, conserved domain sequence characteristics and protein structure comparisons were employed to explore the distribution of RNA N6mA modification (m6A, m6,6A, m6Am, m6, 6Am and m6t6A)-associated proteins (writers, readers and erasers) in three kingdoms of life and reveal the evolutionary history of these modifications. These findings further confirmed that the restriction-modification (R-M) system is the origin of DNA and RNA N6mA modifications. Among them, the existing mRNA m6A modification system derived from the last eukaryotic common ancestor (LECA) is the evolutionary product of elements from the last universal common ancestor (LUCA) or driven by horizontal gene transfer (HGT) from bacterial elements. The subsequent massive gene gains and losses contribute to the development of unique and diverse functions in distinct species. Particularly, RNA methyltransferases (MTases) as the writer responsible for adding N6mA marks on mRNA and ncRNAs may have evolved from class α and β prokaryotic “orphan” MTases originating from the R-M system. The reader, YTH proteins that specifically recognize the m6A deposit, may be acquired by LECA from an individual prokaryotic YTH-domain protein that evolved from N-terminals of an R-M system endonuclease. The eraser, which emerged from the ALKB family (ALKBH5 and FTO) in eukaryotes, may be driven by independent HTG from bacterial ALKB proteins. The evolutionary history of RNA N6mA modifications was inferred in the present study, which will deepen our understanding of these modifications in different species.
Highlights
As described by Francis Crick’s central dogma, RNA is the only direct product of DNA and is subsequently exported from the nucleus to the cytoplasm, where messenger RNAs (mRNAs) is translated into proteins [1,2]
FTO and ALKBH5 are conserved in the major phylum of eukaryotes
Most mRNA m6 A modification-associated proteins were absent in prokaryotes, only with some sporadic m6 A modification components identified in Bacteria or Archaea, such as METTL3/METTL14 in Anabaena PCC 7122, FTO
Summary
As described by Francis Crick’s central dogma, RNA is the only direct product of DNA and is subsequently exported from the nucleus to the cytoplasm, where mRNA is translated into proteins [1,2]. RNA is known to be a key player in transcription, translation and cellular decision-making in the form of noncoding RNAs (ncRNAs), such as rRNAs, tRNAs, microRNAs, piRNAs and long noncoding RNAs [3,4] During these processes, gene activity, expression and function can be regulated by alterations in RNA sequences and by the mechanism that is not associated with any change in the nucleic acid sequence itself, which is referred to as RNA modifications or ‘RNA epigenetics’ [5]. Chemical modifications are found in almost all types of RNA, adding additional complexity to the information carried by RNA These modifications influence the RNA structure and its interaction with other molecules, giving rise to the diverse functions of RNA molecules, especially within complex regulatory networks, where small, subtle structural changes can bring about significant changes in cellular metabolism by affecting mRNA stability, splicing, translational efficiency and pri-microRNA processing, among other processes [6,7]. Among a multitude of RNA modifications, m6 A, one form of methylation at the N6 position of adenosine (N6mA)
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