Diagram of DNA synthesis by Pol ν and a primer-loopout model for trinucleotide-repeat (TNR) expansion. (a) The high-fidelity Pol I and TLS Pol ν differ in the open states, while identical in the closed states. When the O helix in Pol ν is open for dNTP binding, helices Oa and Ob exclude the template base from the active site. The unique K679 in Pol ν further promotes dTTP misincorporation. The 3′–5′ exonuclease (Exo, pink star), which proofreads and improves the accuracy of Pol I, is inactivated in Pol ν (pseudo-Exo, black star). (b) A primer–loopout model. When a downstream template base is unusable (indicated as a red dot), Pol ν can loop out 1–2 nucleotides of the primer strand at the −3 position to re-use the normal template base(s) for lesion-bypass DNA synthesis. The mobile thumb of Pol ν (shown as semi-transparent green) may facilitate DNA translocation and misalignment. (c) Repetitive DNA sequence such as trinucleotide repeats (CNG)n would ease loopout of repeat units, as diagramed here, and result in repeat expansion.