Detection of DNA Modifications by Sequence-Specific Transcription Factors

The establishment, detection, and alteration or elimination of epigenetic DNA modifications are essential to controlling gene expression ranging from bacteria to mammals. The DNA methylations occurring at cytosine and adenine are carried out by SAM-dependent methyltransferases. Successive oxidations of 5-methylcytosine (5mC) by Tet dioxygenases generate 5-hydroxymethyl (5hmC), 5-formyl (5fC), and 5-carboxyl (5caC) derivatives; thus, DNA elements with multiple methylation sites can have a wide range of modification states. In contrast, oxidation of N6-methyladenine by homologs of Escherichia coli AlkB removes the methyl group directly. Both Tet and AlkB enzymes are 2-oxoglutarate- and Fe(II)-dependent dioxygenases. DNA-binding proteins decode the modification status of specific genomic regions. This article centers on two families of sequence-specific transcription factors: bZIP (basic leucine-zipper) proteins, exemplified by the AP-1 and CEBPβ recognition of 5mC; and bHLH (basic helix-loop-helix) proteins, exemplified by MAX and TCF4 recognition of 5caC. We discuss the impact of template strand DNA modification on the activities of DNA and RNA polymerases, and the varied tendencies of modifications to alter base pairing and their interactions with DNA repair enzymes.