Harnessing natural DNA modifying activities for editing of the genome and epigenome

[Display omitted] •Site-specific genome and epigenome editing are rapidly advancing.•Knowledge of DNA-modifying enzymes can be exploited to improve activity.•Editing complexes can be used to directly probe the biology of DNA modifications. The introduction of site-specific DNA modifications to the genome or epigenome presents great opportunities for manipulating biological systems. Such changes are now possible through the combination of DNA-modifying enzymes with targeting modules, including dCas9, that can localize the enzymes to specific sites. In this review, we take a DNA modifying enzyme-centric view of recent advances. We highlight the variety of natural DNA-modifying enzymes—including DNA methyltransferases, oxygenases, deaminases, and glycosylases—that can be used for targeted editing and discuss how insights into the structure and function of these enzymes has further expanded editing potential by introducing enzyme variants with altered activities or by improving spatiotemporal control of modifications.