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Means, mechanisms and consequences of adenine methylation in DNA

Abstract

N6-methyl-2′-deoxyadenosine (6mA or m6dA) has been reported in the DNA of prokaryotes and eukaryotes ranging from unicellular protozoa and algae to multicellular plants and mammals. It has been proposed to modulate DNA structure and transcription, transmit information across generations and have a role in disease, among other functions. However, its existence in more recently evolved eukaryotes remains a topic of debate. Recent technological advancements have facilitated the identification and quantification of 6mA even when the modification is exceptionally rare, but each approach has limitations. Critical assessment of existing data, rigorous design of future studies and further development of methods will be required to confirm the presence and biological functions of 6mA in multicellular eukaryotes.

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Fig. 1: Directed epigenetic DNA methylations.
Fig. 2: Potential modes of 6mA enrichment.
Fig. 3: Biological roles of DNA adenine methylation potentially conserved in unicellular and multicellular organisms.
Fig. 4: Emerging potential roles of 6mA in metazoa.

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Acknowledgements

The work from the Greer laboratory is supported by grants from the NIH (DP2AG055947 and R01AI151215). The authors thank C. He, E. Kool and N. Mosammaparast for helpful discussions. They apologize for the literature omitted owing to space limitations.

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Glossary

Epigenetic

In the context of this article, this term refers to changes to the DNA that do not alter its nucleotide sequence.

Dimroth rearrangement

A passive process by which a methyl group is transferred from the N1 position to the N6 position of the same adenine base.

Nucleotide salvage pathway

The process by which intermediates of nucleotide degradation are recovered to be converted back into nucleotides, bypassing de novo synthesis.

Long-read sequencing

Third-generation sequencing approaches that can generate reads >10,000 bases in length, which improves mapping accuracy compared with short-read approaches; however, long-read approaches have higher error rates at individual bases than short-read methods.

RNA–DNA hybrids

Occur when nascent RNA transcripts hybridize with one strand of the DNA template creating a three-stranded structure called an R loop.

MT-A70 domain

This domain binds to S-adenosylmethionine and is present in a clade of RNA and DNA methyltransferases.

Hemimethylated DNA

Describes a DNA molecule in which only one of the two complementary DNA strands is methylated.

Triple negative breast cancer

Cancers that are negative for oestrogen receptors, progesterone receptors and excess HER2 protein and therefore do not respond to hormonal therapies or targeting of the HER2 receptor.

Epigenomic editing

Engineered changes to the epigenome that do not alter the DNA sequence that are accomplished using a modified Cas9 nuclease.

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Boulias, K., Greer, E.L. Means, mechanisms and consequences of adenine methylation in DNA. Nat Rev Genet 23, 411–428 (2022). https://doi.org/10.1038/s41576-022-00456-x

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