The proposal that N6-methyl-deoxyadenosine (m6dA) acts as an epigenetic mark in mammals remains controversial. Using isotopic labeling coupled to ultrasensitive mass spectrometry, we confirm the presence of low-level m6dA in mammalian DNA. However, the bulk of genomic m6dA originates from ribo-N6-methyladenosine, which is processed via the nucleotide-salvage pathway and misincorporated by DNA polymerases. Our results argue against m6dA acting as a heritable, epigenetic DNA mark in mammalian cells.
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We thank L. Schomacher for discussions, valuable suggestions, including experimental design and feedback during manuscript preparation. We thank M. Pradhan and G. Joshi for discussions, suggestions and critical reading of the manuscript. We are grateful for technical support by S. Ritz from the Institute of Molecular Biology Core Facility Microscopy.
The authors declare no competing interests.
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Musheev, M.U., Baumgärtner, A., Krebs, L. et al. The origin of genomic N6-methyl-deoxyadenosine in mammalian cells. Nat Chem Biol 16, 630–634 (2020). https://doi.org/10.1038/s41589-020-0504-2
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