Polymerase delta (Pol δ) is an enzyme complex found within the nucleus of eukaryotic cells, including human cells. It functions as a molecular “builder” and “repairer” of DNA, creating new DNA strands and fixing existing ones. The polymerase delta complex is composed of four subunits: POLD1, POLD2, POLD3, and POLD4.
Its Primary Role in DNA Replication
DNA replication is the process by which a cell makes an exact copy of its DNA before dividing. This involves unwinding the DNA double helix, creating two single strands that serve as templates for new strands. Polymerase delta has a specific function in synthesizing the “lagging strand” of DNA. While polymerase epsilon primarily handles the leading strand, Pol δ is responsible for synthesizing the lagging strand in segments known as Okazaki fragments.
Pol δ begins synthesizing DNA on the lagging strand after another polymerase, Pol α, lays down a short RNA primer followed by 20-30 deoxynucleotides. It then extends this primer, synthesizing 200-300 bases until it encounters the next primer. This enzyme also possesses a “proofreading” ability, known as 3’→5′ exonuclease activity, which allows it to correct errors by removing incorrectly added nucleotides.
The interaction of Pol δ with proliferating cell nuclear antigen (PCNA), a sliding clamp protein, enhances its ability to synthesize long stretches of DNA without detaching. This collaboration with PCNA and other associated factors, such as replication factor C, allows Pol δ to efficiently displace RNA primers and synthesize new DNA. These combined actions contribute to a very low mutation rate, typically less than one error per genome per replication cycle.
Its Contribution to DNA Repair
DNA is constantly exposed to factors that can cause damage or errors, even after replication. Polymerase delta is involved in several DNA repair pathways, acting as a “cleanup crew” for existing DNA damage. This role is distinct from its function in new DNA synthesis during replication.
Pol δ participates in pathways such as nucleotide excision repair and base excision repair. In these processes, damaged or incorrect nucleotides are removed from the DNA strand, creating a gap. Polymerase delta then fills these single-stranded gaps by synthesizing the correct sequence of DNA. This gap-filling activity is important for restoring the molecule’s integrity.
The enzyme’s ability to polymerize DNA across these gaps helps ensure that the genetic code remains accurate. Its proofreading function, also used in replication, is equally important here, as it helps prevent new errors from being introduced during the repair process.
Ensuring Genome Stability
The combined roles of polymerase delta in accurate DNA replication and efficient DNA repair are important for maintaining the stability and integrity of the human genome. By precisely copying DNA during cell division and actively correcting errors or damage, Pol δ helps prevent the accumulation of mutations. A stable genome ensures genetic information is faithfully passed from one generation of cells to the next, and from parent to offspring.
Failure in Pol δ’s functions, either in replication accuracy or repair efficiency, can lead to an increase in mutations. These accumulated mutations can have broad implications for cellular health and contribute to genetic disorders. For example, mutations in the genes encoding Pol δ subunits have been linked to an increased susceptibility to certain diseases, including some cancers.
Pol δ helps prevent the initiation of malignancies in somatic cells. It also acts to safeguard our genetic information, ensuring cells function correctly and the body maintains overall health.