POLD1

POLD1, or polymerase delta catalytic subunit 1, is a human gene that encodes the catalytic subunit of DNA polymerase delta, the central enzyme responsible for DNA replication in eukaryotic cells. The protein contains the DNA polymerase activity and a 3' to 5' exonuclease proofreading activity, which helps maintain genome integrity by correcting misincorporated nucleotides during DNA synthesis.

During replication, Pol δ forms a holoenzyme with regulatory subunits encoded by POLD2, POLD3, and POLD4, and it interacts with the proliferating cell nuclear antigen (PCNA) clamp and the replication factor C (RFC) clamp loader to achieve high processivity. The enzyme primarily conducts lagging-strand synthesis, though it can contribute to leading-strand replication, and it also participates in several DNA repair pathways, including base excision repair and mismatch repair, helping to correct damage after replication.

Clinically, germline variants in POLD1 cause polymerase proofreading-associated polyposis (PPAP), a hereditary cancer syndrome characterized by multiple colorectal adenomas and an elevated risk of colorectal cancer, and in some families, endometrial cancer. These variants often lie in the exonuclease proofreading domain and reduce fidelity, increasing the mutational burden. Somatic POLD1 mutations have also been observed in various cancers and can accompany a hypermutated tumor phenotype, frequently with alterations in the same exonuclease domain as POLE mutations.

Research areas include the structure-function relationships of the POLD1-containing complex, its interactions with PCNA and RFC, and the consequences of variant POLD1 on replication fidelity and cancer risk. Understanding POLD1 helps illuminate mechanisms of genome maintenance and inherited cancer predisposition.