DNA Damage Tolerance Mechanisms in Eukaryotic Cells
Summary
The duplication of eukaryotic genomes is constantly challenged by lesions arising from endogenous metabolites and environmental agents. DNA damage tolerance (DDT) mechanisms enable replication to progress past such lesions without immediate repair, thereby preventing replication fork collapse and preserving genome integrity. Two principal DDT pathways operate at stalled forks: translesion synthesis (TLS), in which specialised polymerases replicate directly across damaged templates with reduced fidelity, and template switching (TS), an error-free route that harnesses the undamaged sister chromatid as a template. The sliding clamp PCNA orchestrates pathway choice via post-translational modifications—mono-ubiquitination, poly-ubiquitination and SUMOylation—that recruit or inhibit specific factors. In parallel, recombination-mediated processes and fork remodelling by helicases and motor proteins promote lesion bypass and fork restart. Dysregulation of these interconnected pathways is implicated in mutagenesis, carcinogenesis and resistance to therapy, highlighting the global significance of understanding DDT mechanisms.
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DNA Damage Tolerance Mechanisms in Eukaryotic Cells publication trend
The graph below shows the total number of articles in dna damage tolerance mechanisms in eukaryotic cells across all publications each year (not limited to Nature Index journals).
Technical terms
DNA damage tolerance (DDT): Mechanisms allowing DNA replication to continue past lesions without prior repair.
Translesion synthesis (TLS): Damage-bypass pathway employing specialised, low-fidelity polymerases to replicate across DNA lesions.
Template switching (TS): Error-free bypass route that utilises the undamaged sister chromatid as a template for lesion circumvention.
Proliferating cell nuclear antigen (PCNA): Ring-shaped sliding clamp that tethers DNA polymerases and coordinates DDT through post-translational modifications.
Ubiquitination: Covalent attachment of ubiquitin to proteins, regulating PCNA and directing pathway choice in DDT.
Replication fork regression: Reversal of the fork structure to stabilise stalled forks and facilitate lesion bypass or restart.
References
- Effects of PCNA Stability on the Formation of Mutations. International Journal of Molecular Sciences (2024).
- Cell Type Specific Suppression of Hyper-Recombination by Human RAD18 Is Linked to Proliferating Cell Nuclear Antigen K164 Ubiquitination. Biomolecules (2025).
- Mechanisms of DNA Damage Tolerance: Post-Translational Regulation of PCNA. Genes (2018).
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