translesion

Translesion synthesis is a DNA damage tolerance process that enables replication to proceed when the normal high-fidelity DNA polymerases encounter lesions on the template strand. By allowing replication to continue past damaged sites, TLS helps prevent fork collapse and cell death, but it often introduces mutations.

In eukaryotes, TLS relies on specialized DNA polymerases, primarily members of the Y-family (such as polymerases eta, iota, and kappa) and the scaffolding enzyme Rev1, with polymerase zeta (consisting of Rev3L and Rev7) serving as an extender. The process is coordinated by the post-translational modification of proliferating cell nuclear antigen (PCNA); for many lesions, PCNA is monoubiquitinated, which promotes the recruitment of TLS polymerases to the lesion. Insertion opposite the lesion is performed by a TLS polymerase, after which a different polymerase (often Pol zeta) extends from the inserted nucleotide to resume normal replication. TLS is generally error-prone, contributing to mutagenesis and genome instability, although certain polymerases can bypass specific lesions more accurately.

TLS is distinct from error-free damage tolerance pathways, such as template switching, which use the undamaged sister chromatid to bypass lesions without introducing mutations. In bacteria, translesion synthesis is carried out by polymerases such as DinB (Pol IV) and UmuCD (Pol V) and is regulated by the SOS response.

Defects in TLS pathways are associated with human disease. For example, mutations in POLH cause xeroderma pigmentosum variant, highlighting the diverse roles TLS plays in genome maintenance and organismal health.