How a homolog of high-fidelity replicases conducts mutagenic DNA synthesis

All DNA replicases achieve high fidelity by a conserved mechanism, but each translesion polymerase carries out mutagenic DNA synthesis in its own way. Here we report crystal structures of human DNA polymerase. (Pol nu), which is homologous to high-fidelity replicases yet is error prone. Instead of a simple open-to-closed movement of the O helix upon binding of a correct incoming nucleotide, Pol nu has a different open state and requires the finger domain to swing sideways and undergo both opening and closing motions to accommodate the nascent base pair. A single-amino acid substitution in the O helix of the finger domain improves the fidelity of Pol nu nearly ten-fold. A unique cavity and the flexibility of the thumb domain allow Pol nu to generate and accommodate a looped-out primer strand. Primer loop-out may be a mechanism for DNA trinucloetide-repeat expansion.