Translesion Synthesis: Damage Tolerance and Mutagenesis

Swapping the Polymerase

The replicative polymerases have tight active sites that stall at damaged bases. Translesion polymerases such as Pol eta, Pol iota, Pol kappa and REV1, together with the Pol zeta extender, have more open active sites that can accommodate a distorted template.

A key trigger is monoubiquitination of the sliding clamp PCNA at stalled forks, which increases the affinity of translesion polymerases for the primer terminus. After bypass, the high-fidelity polymerase is restored.

Accuracy Depends on the Lesion

Pol eta copies past ultraviolet cyclobutane dimers relatively accurately, which is why its loss causes a variant form of xeroderma pigmentosum with UV sensitivity despite intact excision repair.

For many other lesions the bypass polymerases insert an incorrect base, so translesion synthesis is a major source of point mutations after genotoxic exposure. Post-replicative gaps left opposite lesions can also be filled later by these polymerases.

Relevance to Treatment Resistance

Because translesion synthesis lets cells survive DNA damage from chemotherapy and continue dividing, high pathway activity has been associated in laboratory models with tolerance of platinum and other agents, and with the accelerated mutation accrual seen in drug-tolerant persister cells.

This is preclinical rationale for targeting the pathway, not an established clinical strategy, and no translesion-synthesis inhibitor is a standard treatment.

Reading It on a Tumour Report

Translesion synthesis is not something a clinical report measures or acts on. Its main interpretive relevance is as one explanation for the accelerated, often APOBEC-flavoured mutation accrual seen in drug-tolerant persister cells and in tumours that relapse after a long targeted-therapy response.

Investigational inhibitors of REV1 or Pol zeta aim to blunt chemotherapy-induced mutagenesis and resistance and are in early trials. Until those mature, the pathway is best understood as background biology that shapes how resistance evolves rather than as something to test for.

Key Takeaways

• ·Translesion synthesis tolerates DNA damage by replicating across it with specialised polymerases.
• ·The process is often error-prone and contributes to mutagenesis after genotoxic exposure.
• ·Its role in surviving chemotherapy damage makes it a research target for resistance, not yet a clinical one.