POLD4

POLD4 Full Name

polymerase (DNA-directed), delta 4, accessory subunit

POLD4 Introduction

POLD4, frequently referred to in literature as p12, is the smallest and highly dynamic accessory subunit of the DNA polymerase delta (Pol δ) complex. Pol δ is the primary replicative polymerase responsible for synthesizing the lagging strand during DNA replication and is absolutely indispensable for various critical DNA repair pathways, including base excision repair (BER), nucleotide excision repair (NER), and mismatch repair. Within this complex, POLD4 plays a crucial regulatory role rather than a strictly catalytic one. Under normal conditions, it stabilizes the tetrameric Pol δ complex. However, during periods of severe DNA damage or replication stress, POLD4 undergoes rapid, ubiquitin-mediated proteasomal degradation. This intentional loss of POLD4 converts Pol δ into a trimeric complex, which slows down the replication fork and dramatically alters the enzyme's proofreading efficiency, thereby providing the cell with the necessary time to accurately repair DNA lesions before replication proceeds.

Figure 1. Model and Structure of Yeast and Human Replication DNA Polymerase (Pol) δ Complex. (Source: Fuchs J, et al. 2021)

Clinically, the dysregulation of POLD4 is heavily implicated in genomic instability and oncogenesis. The pathological downregulation or loss of POLD4 compromises the fidelity of DNA repair and causes the accumulation of double-strand breaks. In aggressive malignancies, particularly lung cancer and various squamous cell carcinomas, low expression of POLD4 is frequently observed. This deficiency forces cancer cells to rely on highly error-prone alternative repair pathways, which paradoxically accelerates the mutation rate, drives tumor evolution, and significantly diminishes patient survival rates. Thus, POLD4 serves as a critical guardian of genome stability and a potential prognostic biomarker in oncology.

Alternate Names for POLD4

POLD4; polymerase (DNA-directed), delta 4; DNA polymerase delta subunit 4; DNA polymerase delta smallest subunit p12; p12; POLDS

• 1. Fuchs J, et al. Underappreciated Roles of DNA Polymerase δ in Replication Stress Survival. Trends Genet. 2021 May;37(5):476-487.
  2. Meng X, et al. The p12 subunit of human polymerase delta modulates the rate and fidelity of DNA synthesis. Biochemistry. 2010 May 4;49(17):3545-54.