<p>The helix-hairpin-helix (HhH) motif is an around 20 amino acids domain present in prokaryotic and eukaryotic non-sequence-specific DNA binding proteins. The HhH motif is similar to, but distinct from, the helix-turn-helix (HtH) and the helix-loop-helix (HLH) motifs. All three motifs have two helices (H1 and H2) connected by a short turn. DNA-binding proteins with a HhH structural motif are involved in non-sequence-specific DNA binding that occurs via the formation of hydrogen bonds between protein backbone nitrogens and DNA phosphate groups. These HhH motifs are observed in DNA repair enzymes and in DNA polymerases. By contrast, proteins with a HtH motif bind DNA in a sequence-specific manner through the binding of H2 with the major groove; these proteins are primarily gene regulatory proteins. DNA-binding proteins with the HLH structural motif are transcriptional regulatory proteins and are principally related to a wide array of developmental processes [<cite idref="PUB00015243"/>].</p><p>Examples of proteins that contain a HhH motif include the 5'-exonuclease domains of prokaryotic DNA polymerases [<cite idref="PUB00011715"/>], the eukaryotic/prokaryotic RAD2 family of 5'-3' exonucleases such as T4 RNase H and T5 [<cite idref="PUB00011713"/>, <cite idref="PUB00011714"/>], eukaryotic 5' endonucleases such as FEN-1 (Flap) [<cite idref="PUB00011712"/>], and some viral exonucleases.</p>