Translesion DNA Synthesis Mechanisms in Eukaryotic Cells

Translesion DNA synthesis (TLS) is a specialised branch of the DNA damage tolerance pathway that enables eukaryotic cells to replicate past lesions that would otherwise stall the replication machinery. Under conditions of genotoxic stress, replicative polymerases encounter a variety of DNA adducts—such as UV-induced photoproducts, oxidative lesions and bulky chemical modifications—and are replaced transiently by low-fidelity TLS polymerases. These include the Y-family polymerases (Pol η, ι, κ and Rev1) that insert nucleotides opposite damaged bases, and the B-family polymerase ζ (Pol ζ) that extends from the inserted nucleotide to re-establish a substrate for high-fidelity replication. Recruitment of TLS polymerases is orchestrated by post-translational modification of the sliding clamp PCNA (proliferating cell nuclear antigen), principally monoubiquitination mediated by Rad6–Rad18, which promotes binding of ubiquitin-binding domains present in Y-family enzymes. Rev1 additionally serves as a protein scaffold, physically linking insertion and extension polymerases via specific interaction interfaces. While TLS inherently carries an elevated mutagenic risk, it is essential for tolerating DNA damage, maintaining replication fork progression and preventing catastrophic fork collapse. Failure or misregulation of TLS contributes to genome instability, carcinogenesis and influences cell sensitivity to chemotherapeutic agents.

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Translesion DNA Synthesis Mechanisms in Eukaryotic Cells publication trend

The graph below shows the total number of articles in translesion dna synthesis mechanisms in eukaryotic cells across all publications each year (not limited to Nature Index journals).

Technical terms

Translesion DNA synthesis (TLS): A damage-tolerance process in which specialised low-fidelity polymerases replicate past DNA lesions that stall high-fidelity replicative polymerases.

PCNA monoubiquitination: Post-translational attachment of ubiquitin to PCNA at lysine 164, which promotes recruitment of Y-family TLS polymerases to stalled replication forks.

Y-family polymerases: A group of specialised DNA polymerases (η, ι, κ and Rev1) characterised by spacious active sites that accommodate distorted DNA templates, allowing nucleotide insertion opposite lesions.

Polymerase ζ (Pol ζ): A B-family DNA polymerase composed of a catalytic Rev3 subunit and accessory Rev7 subunit(s) that extends from nucleotides inserted opposite lesions by Y-family enzymes.

Scaffolding: The non-catalytic role of Rev1 in TLS, wherein its C-terminal domain binds other TLS polymerases, coordinating their sequential action at a lesion site.

References

1. USP9X-mediated REV1 deubiquitination promotes lung cancer radioresistance via the action of REV1 as a Rad18 molecular scaffold for cystathionine γ-lyase. Journal of Biomedical Science (2024).
2. The Catalytic Activity of Human REV1 on Undamaged and Damaged DNA. International Journal of Molecular Sciences (2024).
3. DNA polymerase ζ in DNA replication and repair. Nucleic Acids Research (2019).
4. Structural Basis of Rev1-mediated Assembly of a Quaternary Vertebrate Translesion Polymerase Complex Consisting of Rev1, Heterodimeric Polymerase (Pol) ζ, and Pol κ*. Journal of Biological Chemistry (2012).
5. Inhibition of mutagenic translesion synthesis: A possible strategy for improving chemotherapy?. PLOS Genetics (2017).
6. Translesion Synthesis: Insights into the Selection and Switching of DNA Polymerases. Genes (2017).