The origin of genomic N6-methyl-deoxyadenosine in mammalian cells

The proposal that N-6-methyl-deoxyadenosine (m(6)dA) acts as an epigenetic mark in mammals remains controversial. Using isotopic labeling coupled to ultrasensitive mass spectrometry, we confirm the presence of low-level m(6)dA in mammalian DNA. However, the bulk of genomic m(6)dA originates from ribo-N-6-methyladenosine, which is processed via the nucleotide-salvage pathway and misincorporated by DNA polymerases. Our results argue against m(6)dA acting as a heritable, epigenetic DNA mark in mammalian cells.