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Nucleic Acids Res ; 46(22): 11659-11670, 2018 12 14.
Article in English | MEDLINE | ID: mdl-30412255

ABSTRACT

N6-methyldeoxyadenosine (6mA) is a well-characterized DNA modification in prokaryotes but reports on its presence and function in mammals have been controversial. To address this issue, we established the capacity of 6mA-Crosslinking-Exonuclease-sequencing (6mACE-seq) to detect genome-wide 6mA at single-nucleotide-resolution, demonstrating this by accurately mapping 6mA in synthesized DNA and bacterial genomes. Using 6mACE-seq, we generated a human-genome-wide 6mA map that accurately reproduced known 6mA enrichment at active retrotransposons and revealed mitochondrial chromosome-wide 6mA clusters asymmetrically enriched on the heavy-strand. We identified a novel putative 6mA-binding protein in single-stranded DNA-binding protein 1 (SSBP1), a mitochondrial DNA (mtDNA) replication factor known to coat the heavy-strand, linking 6mA with the regulation of mtDNA replication. Finally, we characterized AlkB homologue 1 (ALKBH1) as a mitochondrial protein with 6mA demethylase activity and showed that its loss decreases mitochondrial oxidative phosphorylation. Our results show that 6mA clusters play a previously unappreciated role in regulating human mitochondrial function, despite 6mA being an uncommon DNA modification in the human genome.


Subject(s)
DNA, Mitochondrial/genetics , DNA-Binding Proteins/genetics , DNA/genetics , Deoxyadenosines/genetics , Genome, Mitochondrial , Mitochondrial Proteins/genetics , AlkB Homolog 1, Histone H2a Dioxygenase/genetics , AlkB Homolog 1, Histone H2a Dioxygenase/metabolism , Bacteriophage lambda/genetics , Bacteriophage lambda/metabolism , Base Sequence , Chromosome Mapping , DNA/metabolism , DNA, Mitochondrial/metabolism , DNA-Binding Proteins/metabolism , Deoxyadenosines/metabolism , Escherichia coli/genetics , Escherichia coli/metabolism , Exodeoxyribonucleases , HEK293 Cells , Humans , Mitochondrial Proteins/metabolism , Oxidative Phosphorylation , Salmonella typhimurium/genetics , Salmonella typhimurium/metabolism , Sequence Analysis, DNA , Viral Proteins/chemistry , Viral Proteins/metabolism
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