POLD3
Developmental stage
Expression is cell cycle-dependent, with highest levels in G2/M phase and lowest in G1.
Domain
The PIP-box mediates the interaction with PCNA.
Function
Accessory component of both the DNA polymerase delta complex and the DNA polymerase zeta complex (PubMed:17317665, PubMed:22801543, PubMed:24449906). As a component of the trimeric and tetrameric DNA polymerase delta complexes (Pol-delta3 and Pol-delta4, respectively), plays a role in high fidelity genome replication, including in lagging strand synthesis, and repair. Required for optimal Pol-delta activity. Stabilizes the Pol-delta complex and plays a major role in Pol-delta stimulation by PCNA (PubMed:10219083, PubMed:10852724, PubMed:11595739, PubMed:16510448, PubMed:24035200). Pol-delta3 and Pol-delta4 are characterized by the absence or the presence of POLD4. They exhibit differences in catalytic activity. Most notably, Pol-delta3 shows higher proofreading activity than Pol-delta4 (PubMed:19074196, PubMed:20334433). Although both Pol-delta3 and Pol-delta4 process Okazaki fragments in vitro, Pol-delta3 may also be better suited to fulfill this task, exhibiting near-absence of strand displacement activity compared to Pol-delta4 and stalling on encounter with the 5'-blocking oligonucleotides. Pol-delta3 idling process may avoid the formation of a gap, while maintaining a nick that can be readily ligated (PubMed:24035200). Along with DNA polymerase kappa, DNA polymerase delta carries out approximately half of nucleotide excision repair (NER) synthesis following UV irradiation. In this context, POLD3, along with PCNA and RFC1-replication factor C complex, is required to recruit POLD1, the catalytic subunit of the polymerase delta complex, to DNA damage sites (PubMed:20227374). Under conditions of DNA replication stress, required for the repair of broken replication forks through break-induced replication (BIR) (PubMed:24310611). Involved in the translesion synthesis (TLS) of templates carrying O6-methylguanine or abasic sites performed by Pol-delta4, independently of DNA polymerase zeta (REV3L) or eta (POLH). Facilitates abasic site bypass by DNA polymerase delta by promoting extension from the nucleotide inserted opposite the lesion (PubMed:19074196, PubMed:25628356, PubMed:27185888). Also involved in TLS, as a component of the tetrameric DNA polymerase zeta complex. Along with POLD2, dramatically increases the efficiency and processivity of DNA synthesis of the DNA polymerase zeta complex compared to the minimal zeta complex, consisting of only REV3L and REV7 (PubMed:24449906).
Involvement in disease
Immunodeficiency 122
IMD122
An autosomal recessive, severe immunologic disorder characterized by recurrent viral and bacterial infections of the respiratory tract and skin, appearing in early infancy. Additional clinical features include poor overall growth, global developmental delay with poor motor skills, impaired intellectual development, and poor or absent speech acquisition. Some patients have diffuse skin rash, erythroderma, sensorineural hearing loss, lymphadenopathy, dysmorphic facial features, and tooth abnormalities. Death in early childhood may occur.
None
The disease may be caused by variants affecting the gene represented in this entry.
Post-translational modifications
Ubiquitinated, but not targeted to the proteasome (PubMed:16934752). Sumoylated (PubMed:16934752, PubMed:25218447). Sumoylation with SUMO3 may be predominant (PubMed:16934752).
Phosphorylation at Ser-458 is catalyzed in vitro by PKA. It is thought to decrease the affinity for PCNA and Pol-delta4 processivity (PubMed:22148433). Can also be phosphorylated in vitro by CDK1-cyclin-A complex, as well as CDK2-cyclin-A and CDK2-cyclin-E complexes. PCNA interferes with CDK-cyclin phosphorylation (PubMed:11595739).
Cellular localization
- Cytoplasm
- Nucleus
- Partially colocalizes with PCNA and POLD1 at S phase replication sites (PubMed:11595739). Recruited to DNA damage sites within 2 hours following UV irradiation (PubMed:20227374, PubMed:22801543).
Alternative names
KIAA0039, POLD3, DNA polymerase delta subunit 3, DNA polymerase delta subunit C, DNA polymerase delta subunit p66, DNA polymerase delta subunit p68