Upon encountering a template-strand lesion during DNA replication, high fidelity (HiFi) polymerases (Pols) stall and are replaced by specialized translesion synthesis (TLS) Pols. Generally, TLS Pols have low fidelity but are specialized for faithful insertions opposite lesions. Therefore, extension past the lesion by a TLS Pol should be limited to maintain fidelity. While the first polymerase switch and subsequent lesion bypass have been studied in some detail, the ‘switch-back’ to the HiFi Pol has not been explored. Studies have shown that this switch-back does not always occur at the same position beyond all lesions. Further complicating this process is the occasional presence of multiple TLS Pols contributing to bypass of the same lesion. Here, we explore the kinetic process and structural context for limiting extension by a TLS Pol beyond the lesion. We will focus on this switch-back using a model system from <i>Saccharolobus solfataricus </i>as well as draw parallels with the human TLS system to highlight conserved polymerase behavior between multiple TLS Pols, Pol families, and species.

Beyond the lesion: The switch back to high fidelity synthesis

ACS Fall 2021

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