DNA Polymerase Functions in Repair Pathways

DNA polymerases are central to the faithful duplication and maintenance of the genome. Beyond replication, specialised polymerases are recruited to distinct repair pathways to restore integrity after diverse lesions. In small‐base damage, base excision repair (BER) relies on X family polymerases such as Pol β and Pol λ to perform gap filling and excise sugar remnants via intrinsic lyase activity. Nucleotide excision repair (NER) employs replicative polymerases δ and ε with accessory factors to synthesise longer repair patches. Double‐strand breaks are resolved through non‐homologous end joining (NHEJ), where X family members Pol μ and Pol λ bridge broken ends by template‐dependent gap filling, and through homologous recombination, which engages B family polymerases for strand extension during strand invasion. When replication forks encounter lesions, translesion synthesis polymerases of the Y family—Pol η, Pol ι and Pol κ—bypass damage at the cost of reduced fidelity. Emerging evidence also highlights Pol θ in microhomology‐mediated end joining. Collectively, these studies reveal a complex interplay between polymerase structure, cofactor requirement and protein–protein interactions, ensuring dynamic responses to genomic insults. Understanding these mechanisms underpins novel strategies for cancer therapy, genome editing and biomarker development, reflecting the global importance of polymerase‐mediated repair in human health and disease management.

Research from Nature Portfolio

Recent studies have delivered high‐resolution cryo‐electron microscopy structures of Ku70/80 complexes with X family polymerases λ and μ within non‐homologous end joining assemblies. These structures delineate precise protein–protein interfaces, revealing how BRCT domains of polymerases engage the Ku heterodimer to facilitate recruitment and stabilise broken ends. Functional assays with targeted interface mutants demonstrate that BRCT-mediated contacts are essential for efficient gap filling and cell survival following double-strand breaks. A unified mechanistic model now proposes conserved interaction motifs across the X family that coordinate end synapsis and catalysis within the NHEJ machinery.

DNA Polymerase Functions in Repair Pathways publication trend

The graph below shows the total number of articles in dna polymerase functions in repair pathways across all publications each year (not limited to Nature Index journals).

Technical terms

Base excision repair (BER): A pathway that removes small base lesions by excision of damaged bases, gap filling by polymerases and ligation.

Non-homologous end joining (NHEJ): A repair mechanism that directly ligates DNA double-strand breaks without requiring extensive homology.

dRP lyase activity: The enzymatic removal of a 5′-deoxyribose phosphate group from a repair intermediate during BER.

BRCT domain: A motif found in repair proteins that mediates phosphoprotein binding and assembly of repair complexes.

Translesion synthesis: A process whereby specialised polymerases bypass DNA lesions by incorporating nucleotides opposite damaged bases.

Processivity and fidelity: Measures of how many nucleotides a polymerase adds per binding event and its accuracy in selecting correct nucleotides, respectively.

References

1. Structural and functional insights into the interaction between Ku70/80 and Pol X family polymerases in NHEJ. Nature Communications (2025).
2. For the Better or for the Worse? The Effect of Manganese on the Activity of Eukaryotic DNA Polymerases. International Journal of Molecular Sciences (2023).
3. The enzymatic properties of Arabidopsis thaliana DNA polymerase λ suggest a role in base excision repair. Plant Molecular Biology (2024).
4. Identification of an Intrinsic 5′-Deoxyribose-5-phosphate Lyase Activity in Human DNA Polymerase λ A POSSIBLE ROLE IN BASE EXCISION REPAIR*. Journal of Biological Chemistry (2001).
5. Structural accommodation of ribonucleotide incorporation by the DNA repair enzyme polymerase Mu. Nucleic Acids Research (2017).
6. DNA Polymerases β and λ Mediate Overlapping and Independent Roles in Base Excision Repair in Mouse Embryonic Fibroblasts. PLOS ONE (2010).
7. Implication of DNA Polymerase λ in Alignment-based Gap Filling for Nonhomologous DNA End Joining in Human Nuclear Extracts*. Journal of Biological Chemistry (2003).
8. Decision-making during NHEJ: a network of interactions in human Polμ implicated in substrate recognition and end-bridging. Nucleic Acids Research (2014).
9. DNA-binding determinants promoting NHEJ by human Polµ. Nucleic Acids Research (2012).