N6-methyladenine: A Rare and Dynamic DNA Mark

Chromatin, consisting of deoxyribonucleic acid (DNA) wrapped around histone proteins, facilitates DNA compaction and allows identical DNA code to confer many different cellular phenotypes. This biological versatility is accomplished in large part by post-translational modifications to histones and chemical modifications to DNA. These modifications direct the cellular machinery to expand or compact specific chromatin regions and mark certain regions of the DNA as important for cellular functions. While each of the four bases that make up DNA can be modified (Iyer et al., Prog Mol Biol Transl Sci. 101:25–104, 2011), this chapter will focus on methylation of the 6th position on adenines (6mA). 6mA is a prevalent modification in unicellular organisms and until recently was thought to be restricted to them. A flurry of conflicting studies have proposed that 6mA either does not exist, is present at low levels, or is present at relatively high levels and regulates complex processes in different multicellular eukaryotes. Here, we will briefly describe the history of 6mA, examine its evolutionary conservation, and evaluate the current methods for detecting 6mA. We will discuss the proteins that have been reported to bind and regulate 6mA and examine the known and potential functions of this modification in eukaryotes. Finally, we will close with a discussion of the ongoing debate about whether 6mA exists as a directed DNA modification in multicellular eukaryotes.