Translesion DNA Synthesis in Genome Maintenance

Translesion DNA synthesis (TLS) is a conserved damage-tolerance pathway that enables the replication machinery to traverse template lesions that would otherwise stall high-fidelity polymerases. Specialised Y-family polymerases, notably polymerases η and κ, possess enlarged active sites that accommodate distorted templates and catalyse nucleotide insertion opposite a broad spectrum of DNA adducts. Recruitment of these polymerases is governed by post-translational modification of the sliding clamp proliferating cell nuclear antigen (PCNA), principally monoubiquitination by the E3 ligase RAD18. While TLS prevents lethal replication fork collapse, its inherently low fidelity can introduce mutations, with implications for carcinogenesis, chemoresistance and ageing. Crosstalk between TLS and canonical repair pathways such as mismatch repair shapes lesion bypass fidelity and influences mutational outcomes. Recent advances have clarified how TLS polymerases are targeted to replication forks under basal and stress conditions, how regulatory modifications of both PCNA and the polymerases themselves modulate their access to DNA, and how dysregulation of TLS contributes to tumour evolution and treatment response. This balance between lesion bypass and mutagenesis underpins the essential role of TLS in genome maintenance, cellular survival and therapeutic resistance.

Research from Nature Portfolio

Recent studies have illuminated the mechanistic interplay between mismatch repair and TLS during chemotherapy-induced genotoxic stress. Work on glioblastoma cells treated with temozolomide has shown that RAD18 activation in an MMR-dependent fashion orchestrates error-free bypass of O6-methylguanine lesions while promoting error-prone bypass of other adducts, shaping hypermutation and chemoresistance phenotypes. Seminal findings have also defined SUMOylation of polymerase η as a critical determinant of its constitutive association with replication forks: PIAS1-mediated addition of SUMO to Pol η, bridged by RAD18, directs the enzyme to difficult-to-replicate loci and prevents under-replicated DNA under mild stress. Furthermore, identification of the cancer/testes antigen MAGE-A4 as a RAD18-stabilising partner reveals a tumour-specific reprogramming of ubiquitin signalling that enhances PCNA monoubiquitination and promotes efficient lesion bypass in malignancies.

Translesion DNA Synthesis in Genome Maintenance publication trend

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

Technical terms

Translesion DNA synthesis (TLS): A damage-tolerance mechanism in which specialised low-fidelity polymerases replicate across template lesions to prevent fork collapse.

Proliferating cell nuclear antigen (PCNA): A homotrimeric sliding clamp that encircles DNA, coordinating polymerase processivity and recruiting TLS polymerases upon ubiquitination.

Ubiquitination: Covalent attachment of ubiquitin to lysine residues on target proteins, notably monoubiquitination of PCNA at K164 to signal recruitment of TLS enzymes.

SUMOylation: Reversible conjugation of small ubiquitin-like modifier (SUMO) to proteins such as polymerase η, regulating their localisation and activity at replication forks.

RAD18: An E3 ubiquitin ligase that monoubiquitinates PCNA in response to DNA damage, initiating TLS and coordinating cross-talk with repair pathways.

Polymerase η (Pol η): A Y-family TLS polymerase specialised in bypassing UV-induced cyclobutane pyrimidine dimers with moderate fidelity.

Polymerase κ (Pol κ): A Y-family TLS polymerase that bypasses bulky adducts and contributes to replication fork restart under stress conditions.

Mismatch repair (MMR): A post-replicative repair system that corrects base–base mismatches and insertion/deletion loops, modulating TLS fidelity and mutational spectra.

References

1. Trans-lesion synthesis and mismatch repair pathway crosstalk defines chemoresistance and hypermutation mechanisms in glioblastoma. Nature Communications (2024).
2. Rad18-dependent SUMOylation of human specialized DNA polymerase eta is required to prevent under-replicated DNA. Nature Communications (2016).
3. A neomorphic cancer cell-specific role of MAGE-A4 in trans-lesion synthesis. Nature Communications (2016).
4. The DDUP protein encoded by the DNA damage-induced CTBP1-DT lncRNA confers cisplatin resistance in ovarian cancer. Cell Death & Disease (2023).
5. Translesion polymerase kappa-dependent DNA synthesis underlies replication fork recovery. eLife (2018).