For the Better or for the Worse? The Effect of Manganese on the Activity of Eukaryotic DNA Polymerases.

Abstract

DNA polymerases constitute a versatile group of enzymes that not only perform the essential task of genome duplication but also participate in various genome maintenance pathways, such as base and nucleotide excision repair, non-homologous end-joining, homologous recombination, and translesion synthesis. Polymerases catalyze DNA synthesis via the stepwise addition of deoxynucleoside monophosphates to the 3' primer end in a partially double-stranded DNA. They require divalent metal cations coordinated by active site residues of the polymerase. Mg2+ is considered the likely physiological activator because of its high cellular concentration and ability to activate DNA polymerases universally. Mn2+ can also activate the known DNA polymerases, but in most cases, it causes a significant decrease in fidelity and/or processivity. Hence, Mn2+ has been considered mutagenic and irrelevant during normal cellular function. Intriguingly, a growing body of evidence indicates that Mn2+ can positively influence some DNA polymerases by conferring translesion synthesis activity or altering the substrate specificity. Here, we review the relevant literature focusing on the impact of Mn2+ on the biochemical activity of a selected set of polymerases, namely, Polβ, Polλ, and Polµ, of the X family, as well as Polι and Polη of the Y family of polymerases, where congruous data implicate the physiological relevance of Mn2+ in the cellular function of these enzymes.