DNA Polymerase Mechanisms in Eukaryotic Systems

DNA polymerases in eukaryotic cells constitute a family of specialised enzymes responsible for the accurate duplication and repair of the genome. Replicative polymerases α, δ and ε form the core machinery of nuclear DNA synthesis, coordinating initiation, elongation and maturation of both leading and lagging strands. Polymerase α associates with a primase subunit to synthesise short RNA–DNA primers, which are subsequently extended by polymerase δ on the lagging strand and by polymerase ε on the leading strand. Each replicative polymerase possesses a distinct balance of catalytic speed, processivity and intrinsic fidelity. A 3′→5′ exonuclease activity, present in polymerases δ and ε, provides an essential proofreading function, removing misincorporated nucleotides and thereby enhancing overall replication accuracy. Outside the replicative set, translesion synthesis polymerases bypass DNA lesions that would otherwise stall replication forks; these specialised enzymes tolerate distorted templates at the expense of reduced fidelity. Coordination between high-fidelity and lesion-bypass activities is governed by accessory factors, post-translational modifications and regulated exchange at the replication fork. Beyond replication, DNA polymerases also undertake roles in repair pathways such as base excision repair, nucleotide excision repair and recombination. Their interplay with accessory proteins ensures that replication stress and damage are rectified promptly, safeguarding genome stability. Defects in polymerase function underlie a spectrum of human disorders, from immunodeficiency syndromes to cancer predisposition, emphasising their biomedical importance. Recent structural and single-molecule studies have begun to reveal the dynamic conformational changes that govern nucleotide selection, exonucleolytic editing and polymerase switching, offering new mechanistic insight and therapeutic opportunities.

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Technical terms

Processivity: The capacity of a polymerase to add multiple nucleotides without dissociating from the DNA template.

Proofreading: A 3′→5′ exonuclease function that removes incorrectly incorporated nucleotides to enhance replication fidelity.

Translesion synthesis (TLS): A damage-tolerant mechanism whereby specialised polymerases synthesise DNA across lesions that impede replicative enzymes.

Fidelity: The accuracy with which a polymerase incorporates the correct nucleotide opposite the template base.

Okazaki fragment: A short stretch of DNA synthesised discontinuously on the lagging strand during replication.

References

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3. Exonucleolytic proofreading enhances the fidelity of DNA synthesis by chick embryo DNA polymerase-gamma.. Journal of Biological Chemistry (1988).
4. DNA primase from KB cells. Characterization of a primase activity tightly associated with immunoaffinity-purified DNA polymerase-alpha.. Journal of Biological Chemistry (1984).