POLD1

Replication matrix

POLD1 is a gene that encodes the catalytic subunit of the DNA polymerase delta complex, an enzyme crucial for DNA replication and DNA repair mechanisms in eukaryotic cells. The protein encoded by POLD1 is known as DNA polymerase delta catalytic subunit, or Pol δ1. This enzyme plays a key role in the DNA synthesis of the lagging strand during DNA replication and is involved in processes such as base excision repair, nucleotide excision repair, and mismatch repair.

Function

POLD1, along with other subunits of the DNA polymerase delta complex, is essential for the high fidelity of DNA replication. It possesses both polymerase and 3' to 5' exonuclease activity, which allows it to correct errors during DNA synthesis, thereby ensuring the genetic integrity is maintained through cell divisions. The enzyme's exonuclease activity is crucial for its proofreading ability, making it one of the key players in the prevention of mutations and maintenance of genome stability.

Clinical Significance

Mutations in the POLD1 gene have been associated with several human diseases, including colorectal cancer, endometrial cancer, and a predisposition to cancer in general. These mutations can lead to a loss of proofreading ability of the polymerase, resulting in an increased rate of mutations throughout the genome, which can contribute to tumorigenesis. Additionally, germline mutations in POLD1 have been linked to Mandibular Hypoplasia, Deafness, Progeroid Features, and Lipodystrophy Syndrome (MDPL), a rare disorder characterized by a spectrum of clinical features including premature aging.

Interaction with Other Proteins

POLD1 interacts with several other proteins that are involved in DNA replication and repair, including the proliferating cell nuclear antigen (PCNA), which acts as a sliding clamp and increases the processivity of DNA polymerase delta. Other important interacting partners include the other subunits of the polymerase delta complex, replication factor C (RFC), and replication protein A (RPA), which are essential for the initiation and progression of DNA synthesis.

Research and Therapeutic Potential

Understanding the function and regulation of POLD1 has significant implications for cancer research and the development of therapeutic strategies. Inhibitors targeting the DNA polymerase delta complex, and specifically the POLD1 subunit, are being explored as potential chemotherapeutic agents. By selectively inhibiting the replication of cancer cells, these agents could offer a targeted approach to cancer treatment with potentially fewer side effects than traditional chemotherapy.