POLD3

Summary

POLD3 (DNA polymerase delta 3, accessory subunit, HGNC:20932) is a protein-coding gene on chromosome 11q13.4, encoding DNA polymerase delta subunit 3 (Q15054). Accessory component of both the DNA polymerase delta complex and the DNA polymerase zeta complex. It is a common-essential gene (DepMap: required in 99.9% of cancer cell lines).

This gene encodes the 66-kDa subunit of DNA polymerase delta. DNA polymerase delta possesses both polymerase and 3’ to 5’ exonuclease activity and plays a critical role in DNA replication and repair. The encoded protein plays a role in regulating the activity of DNA polymerase delta through interactions with other subunits and the processivity cofactor proliferating cell nuclear antigen (PCNA). Alternatively spliced transcript variants have been observed for this gene.

Source: NCBI Gene 10714 — RefSeq curated summary.

At a glance

• Gene–disease (curated): immunodeficiency 122 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 14
• Clinical variants (ClinVar): 67 total — 1 likely-pathogenic
• Phenotypes (HPO): 35
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 99.9% of screened cell lines (common-essential)
• MANE Select transcript: NM_006591

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20932
Approved symbol	POLD3
Name	DNA polymerase delta 3, accessory subunit
Location	11q13.4
Locus type	gene with protein product
Status	Approved
Aliases	P66, KIAA0039, P68, PPP1R128
Ensembl gene	ENSG00000077514
Ensembl biotype	protein_coding
OMIM	611415
Entrez	10714

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 9 protein_coding, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000263681, ENST00000524752, ENST00000527458, ENST00000528481, ENST00000530163, ENST00000530511, ENST00000531615, ENST00000532497, ENST00000532784, ENST00000532954, ENST00000935603

RefSeq mRNA: 2 — MANE Select: NM_006591 NM_001363597, NM_006591

CCDS: CCDS8233, CCDS86228

Canonical transcript exons

ENST00000263681 — 12 exons

Exon	Start	End
ENSE00001039036	74625408	74625573
ENSE00001039037	74620017	74620089
ENSE00001039041	74629217	74629323
ENSE00001039046	74618537	74618804
ENSE00001299884	74640564	74643076
ENSE00002198152	74592582	74592718
ENSE00003472241	74634583	74634695
ENSE00003546052	74611499	74611538
ENSE00003553153	74636197	74636275
ENSE00003563921	74594061	74594116
ENSE00003601709	74612878	74613010
ENSE00003655011	74604692	74604794

Expression profiles

Bgee: expression breadth ubiquitous, 276 present calls, max score 92.28.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.1491 / max 227.7270, expressed in 1734 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
115855	11.8269	1730
115854	0.2606	79
115853	0.0617	20

Top tissues by expression

291 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	92.28	gold quality
ventricular zone	UBERON:0003053	91.98	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	90.81	gold quality
sperm	CL:0000019	90.15	gold quality
ganglionic eminence	UBERON:0004023	89.40	gold quality
embryo	UBERON:0000922	88.79	gold quality
oocyte	CL:0000023	88.49	gold quality
male germ cell	CL:0000015	88.37	gold quality
rectum	UBERON:0001052	88.36	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	87.59	gold quality
monocyte	CL:0000576	87.44	gold quality
mononuclear cell	CL:0000842	87.31	gold quality
leukocyte	CL:0000738	86.91	gold quality
nephron tubule	UBERON:0001231	86.50	gold quality
bronchial epithelial cell	CL:0002328	86.15	gold quality
right uterine tube	UBERON:0001302	85.96	gold quality
epithelium of bronchus	UBERON:0002031	85.88	gold quality
esophagus squamous epithelium	UBERON:0006920	85.73	gold quality
mucosa of sigmoid colon	UBERON:0004993	85.60	gold quality
bronchus	UBERON:0002185	85.35	gold quality
testis	UBERON:0000473	85.11	gold quality
body of pancreas	UBERON:0001150	84.87	gold quality
right testis	UBERON:0004534	84.82	gold quality
left testis	UBERON:0004533	84.49	gold quality
calcaneal tendon	UBERON:0003701	84.39	gold quality
vermiform appendix	UBERON:0001154	84.32	gold quality
superficial temporal artery	UBERON:0001614	84.22	silver quality
colonic mucosa	UBERON:0000317	83.98	gold quality
pancreas	UBERON:0001264	83.93	gold quality
colonic epithelium	UBERON:0000397	83.92	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.22

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

131 targeting POLD3, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-512-3P	99.97	67.35	1049
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548C-5P	99.94	71.24	3488
HSA-MIR-548D-5P	99.94	71.23	3502
HSA-MIR-548H-5P	99.94	71.24	3488
HSA-MIR-548I	99.94	71.25	3481

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 99.9% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 22)

• show that there is a direct interaction between p66 and PCNA in living cells during DNA replication. The dominant negative effect upon growth resulting from expression of p66 sub-domains confirms that the p66-PCNA interaction is essential in vivo. (PMID:16000169)
• POLD3, plays a crucial role in the efficient recycling of PCNA during dissociation-association cycles of pol delta during elongation phase of DNA replication. (PMID:17932049)
• Taken together, the results provide evidence that concurrent phosphorylation events in p66 may positively and negatively regulate its activity and interactions with other components of the replisome during the cell cycle. (PMID:18157942)
• As a first step towards understanding the functional importance of their regulatory subunit interactions, the three-dimensional structure of the p50-p66 heterodimer of human Pol delta has been solved using X-ray crystallography. (PMID:18765914)
• the crystal structure of p50*p66(N) complex featuring oligonucleotide binding and phosphodiesterase domains in winged helix-turn-helix N-terminal domain in p66 (PMID:18818516)
• Serine-458, located in the proliferating cell nuclear antigen (PCNA)-interacting motif of Poldelta(p68), is a phosphorylation site for protein kinase A (PKA); p68 mutation results in decreased p68 affinity for PCNA as well as processivity of Poldelta. (PMID:22148433)
• We identified three new CRC risk loci at 6p21 (rs1321311, near CDKN1A; P = 1.14 x 10(-10)), 11q13.4 (rs3824999, intronic to POLD3; P = 3.65 x 10(-10)) and Xp22.2 (rs5934683, near SHROOM2; P = 7.30 x 10(-10)). (PMID:22634755)
• Pol delta3 is the predominant form of Pol delta at sites of UV damage as a result of p12 degradation; results show that Pol delta at the DNA damage site is the Pol delta trimer lacking p12 regardless of the cell cycle phase (PMID:22801543)
• Findings provide evidence for the novel concept that Pol delta3 has a role in lagging strand synthesis, and that both forms of Pol delta3 and 4 may participate in DNA replication in higher eukaryotic cells. (PMID:24035200)
• In a cyclin E overexpression model of DNA replication stress, POLD3, the human ortholog of POL32, was required for cell cycle progression and processive DNA synthesis. (PMID:24310611)
• POLD3 is SUMOylated by SUMO2 in response to replication stress and could play an important role in the regulation of cellular response to DNA replication stress. (PMID:25497329)
• Studies indicate that DNA polymerase delta 3 (Pol delta3) exhibits significant differences in properties with a major impact on cellular processes in genomic surveillance, DNA replication and DNA repair. (PMID:26916162)
• Data suggest that relatively high affinity binding of PolD3-RIR motif to Rev1-C-terminal domain displaces subunits from PolN, Pol-iota, or PolK from Rev1 complex and promotes formation of Rev1/PolZ4 assembly with PCNA for translesion DNA replication. (PMID:26982350)
• data support Poldelta contributing to translesion synthesis in vivo and suggest that the mutagenesis resulting from loss of Poldelta proofreading activity may in part be explained by enhanced lesion bypass (PMID:27185888)
• findings demonstrate a key role of POLD1 and POLD3 in genome stability and S-phase progression revealing RNA-DNA hybrids-dependent effects for POLD3 that might be partly due to its Pol zeta interaction. (PMID:27974823)
• The mitotic DNA synthesis is RAD52 dependent, and RAD52 is required for the timely recruitment of MUS81 and POLD3 to common fragile sites in early mitosis. (PMID:27984745)
• The proofreading activity of DNA polymerase delta plays a role in shunting DNA mismatch repair to an EXO1-dependent excision pathway as opposed to directly participating in gap formation via its 3’-5’ exonuclease activity. (PMID:28934474)
• ROS-induced telomeric R-loops promote repair of telomeric DSBs through CSB-RAD52-POLD3-mediated BIR, a previously unknown pathway protecting telomeres from ROS. ROS-induced telomeric SSBs may not only give rise to DSBs indirectly, but also promote DSB repair by inducing R-loops, revealing an unexpected interplay between distinct ROS-induced DNA lesions. (PMID:31777915)
• Polymerase delta promotes chromosomal rearrangements and imprecise double-strand break repair. (PMID:33077594)
• Interaction of CCND2, CDKN1A, and POLD3 Variants in Mexican Patients with Colorectal Cancer. (PMID:35786622)
• Interaction of human HelQ with DNA polymerase delta halts DNA synthesis and stimulates DNA single-strand annealing. (PMID:36718939)
• POLD3 deficiency is associated with severe combined immunodeficiency, neurodevelopmental delay, and hearing impairment. (PMID:37030525)

Cross-species orthologs

0 orthologs

Protein

Protein identifiers

DNA polymerase delta subunit 3 — Q15054 (reviewed: Q15054)

Alternative names: DNA polymerase delta subunit C, DNA polymerase delta subunit p66, DNA polymerase delta subunit p68

All UniProt accessions (6): Q15054, E9PM91, E9PNC0, E9PRK3, H0YD46, H0YEX7

UniProt curated annotations — full annotation on UniProt →

Function. Accessory component of both the DNA polymerase delta complex and the DNA polymerase zeta complex. 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. 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. 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. 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. Under conditions of DNA replication stress, required for the repair of broken replication forks through break-induced replication (BIR). 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. 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.

Subunit / interactions. Component of both the DNA polymerase delta and DNA polymerase zeta complexes. The tetrameric DNA polymerase delta complex (Pol-delta4), which consists of POLD1/p125, POLD2/p50, POLD3/p66/p68 and POLD4/p12, with POLD1 bearing DNA polymerase and 3’ to 5’ proofreading exonuclease activities. Within this complex, directly interacts with POLD2. Following stress caused by DNA damaging agents or by replication stress, POLD4 is degraded and Pol-delta4 is converted into a trimeric form of the complex (Pol-delta3), which consists of POLD1, POLD2 and POLD3. Pol-delta3 is the major form occurring at S phase replication sites, as well as DNA damage sites. Directly interacts with PCNA, as do POLD1 and POLD4; this interaction stimulates Pol-delta polymerase activity. POLD3 phosphorylation at Ser-458 impairs PCNA binding. Component of the DNA polymerase zeta complex (POLZ), which consists of REV3L, MAD2L2, POLD2 and POLD3, with REV3L bearing DNA polymerase catalytic activity. The DNA polymerase delta complex interacts with POLDIP2; this interaction is probably mediated through direct binding to POLD2. Interacts with REV1 (via C-terminal domain).

Subcellular location. Cytoplasm. Nucleus.

Post-translational modifications. Ubiquitinated, but not targeted to the proteasome. Sumoylated. Sumoylation with SUMO3 may be predominant. Phosphorylation at Ser-458 is catalyzed in vitro by PKA. It is thought to decrease the affinity for PCNA and Pol-delta4 processivity. 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.

Disease relevance. Immunodeficiency 122 (IMD122) [MIM:620869] 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. The disease may be caused by variants affecting the gene represented in this entry.

Domain organisation. The PIP-box mediates the interaction with PCNA.

Isoforms (3)

UniProt ID	Names	Canonical?
Q15054-1	1	yes
Q15054-2	2
Q15054-3	3

RefSeq proteins (2): NP_001350526, NP_006582* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR019038	POLD3	Family
IPR041913	POLD3_sf	Homologous_superfamily

Pfam: PF09507

UniProt features (52 total): modified residue 8, helix 7, mutagenesis site 6, compositionally biased region 5, region of interest 5, cross-link 5, strand 5, sequence variant 4, splice variant 2, turn 2, initiator methionine 1, chain 1, short sequence motif 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
1U76	X-RAY DIFFRACTION	2.6
3E0J	X-RAY DIFFRACTION	3
6TNY	ELECTRON MICROSCOPY	3.08
9EKB	ELECTRON MICROSCOPY	3.65
6TNZ	ELECTRON MICROSCOPY	4.05
6S1M	ELECTRON MICROSCOPY	4.27
6S1N	ELECTRON MICROSCOPY	4.86
6S1O	ELECTRON MICROSCOPY	8.1
2N1G	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15054-F1	63.65	0.32

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (13): 2, 277, 307, 407, 409, 411, 413, 458, 258, 258, 261, 433, 433

Mutagenesis-validated functional residues (6):

Position	Phenotype
258	partially loss of sumoylation. complete loss of sumoylation; when associated with r-433.
325	no effect on sumoylation.
433	partially loss of sumoylation. complete loss of sumo3-sumoylation; when associated with r-285.
456–466	complete loss of pcna binding.
458	partial loss of pcna binding (60% of wild-type) and strong decrease of pcna stimulation of pol-delta4 polymerase activit
459–463	complete loss of pcna binding.

Function

Pathways and Gene Ontology

Reactome pathways

17 pathways

ID	Pathway
R-HSA-110314	Recognition of DNA damage by PCNA-containing replication complex
R-HSA-174411	Polymerase switching on the C-strand of the telomere
R-HSA-174414	Processive synthesis on the C-strand of the telomere
R-HSA-174417	Telomere C-strand (Lagging Strand) Synthesis
R-HSA-174437	Removal of the Flap Intermediate from the C-strand
R-HSA-5358565	Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha)
R-HSA-5358606	Mismatch repair (MMR) directed by MSH2:MSH3 (MutSbeta)
R-HSA-5651801	PCNA-Dependent Long Patch Base Excision Repair
R-HSA-5656169	Termination of translesion DNA synthesis
R-HSA-5685942	HDR through Homologous Recombination (HRR)
R-HSA-5696397	Gap-filling DNA repair synthesis and ligation in GG-NER
R-HSA-5696400	Dual Incision in GG-NER
R-HSA-6782135	Dual incision in TC-NER
R-HSA-6782210	Gap-filling DNA repair synthesis and ligation in TC-NER
R-HSA-69091	Polymerase switching
R-HSA-69166	Removal of the Flap Intermediate
R-HSA-69183	Processive synthesis on the lagging strand

MSigDB gene sets: 397 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_UP, E2F_Q4, REACTOME_DNA_REPLICATION, E2F4DP1_01, GOBP_CELLULAR_RESPONSE_TO_UV, FISCHER_G1_S_CELL_CYCLE, CROONQUIST_NRAS_SIGNALING_DN, GOBP_CELLULAR_RESPONSE_TO_LIGHT_STIMULUS, GOBP_DNA_STRAND_ELONGATION_INVOLVED_IN_DNA_REPLICATION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, DITTMER_PTHLH_TARGETS_UP, MITSIADES_RESPONSE_TO_APLIDIN_DN, GOBP_DNA_DAMAGE_TOLERANCE, RIZKI_TUMOR_INVASIVENESS_3D_DN

GO Biological Process (11): DNA synthesis involved in DNA repair (GO:0000731), DNA-templated DNA replication (GO:0006261), DNA strand elongation involved in DNA replication (GO:0006271), nucleotide-excision repair, DNA gap filling (GO:0006297), mismatch repair (GO:0006298), error-prone translesion synthesis (GO:0042276), DNA biosynthetic process (GO:0071897), DNA synthesis involved in UV-damage excision repair (GO:1904161), DNA replication (GO:0006260), DNA repair (GO:0006281), DNA damage response (GO:0006974)

GO Molecular Function (3): protein-macromolecule adaptor activity (GO:0030674), DNA-directed DNA polymerase activity (GO:0003887), protein binding (GO:0005515)

GO Cellular Component (6): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), zeta DNA polymerase complex (GO:0016035), delta DNA polymerase complex (GO:0043625), nucleus (GO:0005634), nuclear lumen (GO:0031981)

Reactome top-level categories

Rollup of top-13 pathways:

Category	Pathways
Telomere C-strand (Lagging Strand) Synthesis	2
Mismatch Repair	2
Global Genome Nucleotide Excision Repair (GG-NER)	2
Transcription-Coupled Nucleotide Excision Repair (TC-NER)	2
Lagging Strand Synthesis	2
DNA Damage Bypass	1
Extension of Telomeres	1
Processive synthesis on the C-strand of the telomere	1
Resolution of AP sites via the multiple-nucleotide patch replacement pathway	1
Translesion synthesis by Y family DNA polymerases bypasses lesions on DNA template	1
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	1
Leading Strand Synthesis	1
Processive synthesis on the lagging strand	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
DNA metabolic process	4
DNA repair	2
DNA biosynthetic process	2
DNA replication	2
cellular anatomical structure	2
DNA polymerase complex	2
DNA-templated DNA replication	1
DNA strand elongation	1
DNA synthesis involved in DNA replication	1
nucleotide-excision repair	1
translesion synthesis	1
nucleic acid biosynthetic process	1
DNA synthesis involved in DNA repair	1
UV-damage excision repair	1
DNA damage response	1
cellular response to stress	1
protein binding	1
molecular adaptor activity	1
DNA polymerase activity	1
binding	1
nuclear lumen	1
intracellular anatomical structure	1
nuclear replisome	1
nuclear protein-containing complex	1
intracellular membrane-bounded organelle	1
nucleus	1
intracellular organelle lumen	1

Protein interactions and networks

STRING

1646 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
POLD3	POLD2	P49005	999
POLD3	POLD1	P28340	998
POLD3	POLD4	Q9HCU8	989
POLD3	REV3L	O60673	974
POLD3	MAD2L2	Q9UI95	973
POLD3	REV1	Q9UBZ9	800
POLD3	LIG1	P18858	713
POLD3	MUS81	Q96NY9	640
POLD3	RAD51	Q06609	635
POLD3	RAD52	P43351	618
POLD3	POLE2	P56282	612
POLD3	WRN	Q14191	589
POLD3	POLE	Q07864	587
POLD3	SLX4	Q8IY92	587
POLD3	RFC5	P40937	574

IntAct

104 interactions, top by confidence:

A	B	Type	Score
POLD1	POLD2	psi-mi:“MI:0914”(association)	0.910
POLD2	POLD1	psi-mi:“MI:0914”(association)	0.910
POLD1	POLD2	psi-mi:“MI:0915”(physical association)	0.910
POLD4	POLD1	psi-mi:“MI:0914”(association)	0.900
POLD3	POLD1	psi-mi:“MI:0914”(association)	0.900
POLD2	POLD3	psi-mi:“MI:0407”(direct interaction)	0.890
POLD3	POLD2	psi-mi:“MI:0915”(physical association)	0.890
POLD2	POLD3	psi-mi:“MI:0915”(physical association)	0.890
PCNA	POLD3	psi-mi:“MI:0407”(direct interaction)	0.870
PCNA	POLD3	psi-mi:“MI:0915”(physical association)	0.870
POLD3	PCNA	psi-mi:“MI:0915”(physical association)	0.870
PCNA	POLD3	psi-mi:“MI:2364”(proximity)	0.870
PCNA	POLD3	psi-mi:“MI:0403”(colocalization)	0.870
SLC1A1	AGPAT2	psi-mi:“MI:0914”(association)	0.640
PCNA	POM121C	psi-mi:“MI:0914”(association)	0.550
POLD2	REV3L	psi-mi:“MI:0914”(association)	0.530
APLNR	SLC33A1	psi-mi:“MI:0914”(association)	0.530
AFG2A	RFC1	psi-mi:“MI:0915”(physical association)	0.500
WRNIP1	POLD1	psi-mi:“MI:0914”(association)	0.500
DDX21	MED19	psi-mi:“MI:2364”(proximity)	0.480

BioGRID (145): POLD3 (Affinity Capture-MS), POLD3 (Synthetic Growth Defect), POLD3 (Reconstituted Complex), POLD3 (Affinity Capture-MS), POLD3 (Affinity Capture-MS), POLD3 (Affinity Capture-MS), POLD3 (Affinity Capture-MS), POLD3 (Affinity Capture-MS), POLD3 (Affinity Capture-MS), POLD3 (Co-crystal Structure), POLD3 (Reconstituted Complex), POLD3 (Affinity Capture-MS), POLD3 (Negative Genetic), POLD3 (Negative Genetic), POLD3 (Negative Genetic)

ESM2 similar proteins: A2A791, A2YEZ6, A3BDI8, B5DF11, E6ZGB4, O15164, O75151, O75376, O76080, O88878, O88974, P49140, P55265, Q02395, Q08BR4, Q15047, Q15054, Q3SZY7, Q3UWM4, Q4KKX4, Q4V7W5, Q56R14, Q5JSH3, Q5R7S6, Q5U2T3, Q5VZL5, Q5ZK28, Q60974, Q64127, Q6DGF4, Q6FIF0, Q6INA9, Q6P949, Q6PFK1, Q6ZMT4, Q80TJ7, Q86XZ4, Q8CGC4, Q8K1N4, Q8QG78

Diamond homologs: G0S636, P30261, P84798, Q15054, Q9EQ28, Q5ZK28

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
PRKACA	down-regulates	POLD3	phosphorylation
POLD3	“form complex”	“DNA polymerase delta”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 113 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
PCNA-Dependent Long Patch Base Excision Repair	5	38.2×	3e-05
Gap-filling DNA repair synthesis and ligation in GG-NER	5	32.3×	3e-05
Polymerase switching on the C-strand of the telomere	5	31.1×	3e-05
Recognition of DNA damage by PCNA-containing replication complex	5	28.0×	4e-05
Termination of translesion DNA synthesis	5	25.4×	4e-05
Dual Incision in GG-NER	5	19.1×	1e-04
HDR through Homologous Recombination (HRR)	5	14.0×	6e-04
Gap-filling DNA repair synthesis and ligation in TC-NER	5	13.1×	8e-04

GO biological processes:

GO term	Partners	Fold	FDR
DNA-templated DNA replication	6	35.5×	9e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

67 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	50
Likely benign	1
Benign	5

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
3250357	NM_006591.3(POLD3):c.1118A>C (p.Lys373Thr)	Likely pathogenic

SpliceAI

2067 predictions. Top by Δscore:

Variant	Effect	Δscore
11:74592714:AGATC:A	donor_gain	1.0000
11:74592715:GATC:G	donor_gain	1.0000
11:74592715:GATCG:G	donor_gain	1.0000
11:74592717:TC:T	donor_gain	1.0000
11:74592719:G:GG	donor_gain	1.0000
11:74592727:C:G	donor_gain	1.0000
11:74592914:G:GT	donor_gain	1.0000
11:74594117:G:GG	donor_gain	1.0000
11:74604684:T:A	acceptor_gain	1.0000
11:74604791:TTCC:T	donor_gain	1.0000
11:74604795:G:GG	donor_gain	1.0000
11:74611497:A:AG	acceptor_gain	1.0000
11:74611498:G:GA	acceptor_gain	1.0000
11:74611498:GT:G	acceptor_gain	1.0000
11:74612876:A:AG	acceptor_gain	1.0000
11:74612877:G:GC	acceptor_gain	1.0000
11:74612877:GC:G	acceptor_gain	1.0000
11:74612877:GCA:G	acceptor_gain	1.0000
11:74612877:GCAGT:G	acceptor_gain	1.0000
11:74613007:GCAA:G	donor_gain	1.0000
11:74613009:AA:A	donor_gain	1.0000
11:74613010:AG:A	donor_loss	1.0000
11:74613011:G:GG	donor_gain	1.0000
11:74613012:T:A	donor_loss	1.0000
11:74618528:T:A	acceptor_gain	1.0000
11:74618535:A:AG	acceptor_gain	1.0000
11:74618536:G:GA	acceptor_gain	1.0000
11:74618536:GATTT:G	acceptor_gain	1.0000
11:74618802:AAT:A	donor_gain	1.0000
11:74618803:AT:A	donor_gain	1.0000

AlphaMissense

3073 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:74592699:T:A	V14D	1.000
11:74594114:A:C	K38N	1.000
11:74594114:A:T	K38N	1.000
11:74604697:T:C	L41P	1.000
11:74612922:A:C	S102R	1.000
11:74612924:C:A	S102R	1.000
11:74612924:C:G	S102R	1.000
11:74594062:T:A	V21E	0.999
11:74594065:C:T	T22I	0.999
11:74594077:T:C	L26P	0.999
11:74594079:A:C	S27R	0.999
11:74594081:C:A	S27R	0.999
11:74594081:C:G	S27R	0.999
11:74594109:G:C	A37P	0.999
11:74594110:C:A	A37D	0.999
11:74594113:A:T	K38I	0.999
11:74604697:T:A	L41Q	0.999
11:74604756:T:G	Y61D	0.999
11:74611511:G:C	A78P	0.999
11:74612907:A:C	S97R	0.999
11:74612909:C:A	S97R	0.999
11:74612909:C:G	S97R	0.999
11:74612917:T:A	V100E	0.999
11:74612919:T:G	Y101D	0.999
11:74592687:T:A	I10K	0.998
11:74594065:C:A	T22K	0.998
11:74594067:T:G	Y23D	0.998
11:74594072:A:C	K24N	0.998
11:74594072:A:T	K24N	0.998
11:74594073:T:A	W25R	0.998

dbSNP variants (sampled 300 via entrez): RS1000079058 (11:74618393 A>G), RS1000102554 (11:74647145 C>G), RS1000133184 (11:74618596 C>T), RS1000134231 (11:74656388 A>G), RS1000168060 (11:74648399 A>G,T), RS1000180384 (11:74605819 T>A), RS1000295440 (11:74612139 C>A,T), RS1000299482 (11:74628286 A>G), RS1000303129 (11:74665894 C>G), RS1000354945 (11:74665524 C>A,T), RS1000368865 (11:74650312 A>G), RS1000470537 (11:74658634 T>C), RS1000481455 (11:74643208 G>A,T), RS1000579564 (11:74626483 T>C), RS1000607141 (11:74636633 G>A)

Disease associations

OMIM: gene MIM:611415 | disease phenotypes: MIM:620869

GenCC curated gene-disease

Disease	Classification	Inheritance
immunodeficiency 122	Strong	Autosomal recessive
hearing loss disorder	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
immunodeficiency 122	Limited	AR

Mondo (2): immunodeficiency 122 (MONDO:0971151), hearing loss disorder (MONDO:0005365)

Orphanet (0):

HPO phenotypes

35 total (30 of 35 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000407	Sensorineural hearing impairment
HP:0000958	Dry skin
HP:0001019	Erythroderma
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001596	Alopecia
HP:0001744	Splenomegaly
HP:0001880	Increased total eosinophil count
HP:0001999	Abnormal facial shape
HP:0002007	Frontal bossing
HP:0002110	Bronchiectasis
HP:0002240	Hepatomegaly
HP:0002716	Lymphadenopathy
HP:0002718	Recurrent bacterial infections
HP:0002783	Recurrent lower respiratory tract infections
HP:0002788	Recurrent upper respiratory tract infections
HP:0003212	Increased circulating IgE concentration
HP:0003593	Infantile onset
HP:0004315	Decreased circulating IgG concentration
HP:0004429	Recurrent viral infections
HP:0004430	Severe combined immunodeficiency
HP:0005359	Aplasia of the thymus
HP:0005403	Decreased total T cell count
HP:0006297	Enamel hypoplasia
HP:0008404	Nail dystrophy
HP:0010975	Abnormal B cell count
HP:0011968	Feeding difficulties
HP:0031430	Oligoclonal T cell expansion
HP:0032126	Decreased unswitched memory B cell proportion

GWAS associations

14 associations (top):

Study	Trait	p-value
GCST001544_2	Colorectal cancer	4.000000e-10
GCST002919_11	Colorectal cancer	8.000000e-11
GCST003017_16	Colorectal cancer	1.000000e-06
GCST003253_9	Microalbuminuria	9.000000e-06
GCST003791_6	Response to metformin (IC50)	6.000000e-06
GCST005235_1	Hand grip strength	5.000000e-13
GCST005830_130	Hand grip strength	9.000000e-10
GCST006630_29	Diastolic blood pressure	6.000000e-10
GCST007552_29	Colorectal cancer	3.000000e-06
GCST007856_13	Colorectal cancer or advanced adenoma	3.000000e-06
GCST007856_38	Colorectal cancer or advanced adenoma	1.000000e-20
GCST007856_6	Colorectal cancer or advanced adenoma	1.000000e-18
GCST009869_57	Colorectal cancer	1.000000e-06
GCST010276_5	Renal underexcretion gout	4.000000e-07

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0006952	cytotoxicity measurement
EFO:0006941	grip strength measurement
EFO:0006336	diastolic blood pressure

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2260 (SINGLE PROTEIN), CHEMBL2363042 (PROTEIN FAMILY)

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.80	Kd	1.573	nM	CHEMBL3752910
8.80	ED50	1.573	nM	CHEMBL3752910

PubChem BioAssay actives

1 with measured affinity, of 2 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149915: Binding affinity to human POLD3 incubated for 45 mins by Kinobead based pull down assay	kd	0.0016	uM

CTD chemical–gene interactions

58 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, decreases methylation, decreases reaction	4
sodium arsenite	decreases expression, increases expression	3
Valproic Acid	affects cotreatment, increases expression	3
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Tetrachlorodibenzodioxin	affects expression, increases expression	2
Cyclosporine	decreases expression, increases expression	2
Cadmium Chloride	decreases expression, increases expression	2
FR900359	decreases phosphorylation	1
bisphenol F	affects cotreatment, increases expression	1
4-biphenylamine	decreases expression, decreases reaction	1
2,2’-methylenebis(4-methyl-6-tert-butylphenol)	affects response to substance, affects expression	1
trichostatin A	affects expression	1
arsenite	decreases reaction, affects binding	1
manganese chloride	increases abundance, increases expression	1
sulindac sulfide	decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	increases expression, affects cotreatment	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression, increases expression	1
trans-10,cis-12-conjugated linoleic acid	decreases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression, increases expression	1
incobotulinumtoxinA	decreases expression	1
NSC 689534	affects binding, decreases expression	1
Resveratrol	increases expression, affects cotreatment	1
Sunitinib	decreases expression	1
Arsenic Trioxide	increases expression	1
Troglitazone	decreases expression	1
Acetaminophen	increases expression	1
Glyphosate	decreases expression	1
Air Pollutants	affects expression, increases abundance	1
Azathioprine	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652957	Binding	Binding affinity to human POLD3 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

195 cell lines: 194 cancer cell line, 1 induced pluripotent stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_0336	Huh-7	Cancer cell line	Male
CVCL_2957	Huh-7D12	Cancer cell line	Male
CVCL_4W53	Huh7S1	Cancer cell line	Male
CVCL_7927	Huh-7.5	Cancer cell line	Male
CVCL_A0TI	Huh-7.5 Tet-On	Cancer cell line	Male
CVCL_A5AV	Huh7.93	Cancer cell line	Male
CVCL_B7TI	HUH7-R	Cancer cell line	Male
CVCL_B7TJ	HUH7-R-LUC	Cancer cell line	Male
CVCL_C0FW	CHUSJi001-A	Induced pluripotent stem cell	Male
CVCL_C2UW	Huh-7.5 STAT1 KO #1	Cancer cell line	Male

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00205881	PHASE4	COMPLETED	Bilateral Benefit in Adult Users of the HiRes 90K Bionic Ear System
NCT00331539	PHASE4	UNKNOWN	Relationship Between Auto NRT and Behavioural T & C Levels With the Nucleus Freedom Cochlear Implant
NCT00424307	PHASE4	UNKNOWN	Bilateral Cochlear Implant Benefit in Young Children
NCT00765635	PHASE4	COMPLETED	Chlorobutanol, Potassium Carbonate, and Irrigation in Cerumen Removal
NCT03321006	PHASE4	COMPLETED	Treating Hearing Loss to Improve Mood and Cognition in Older Adults
NCT01499901	PHASE3	WITHDRAWN	Comparison of the Bilateral Sequential and Simultaneous Cochlear Implantation in the Deaf Children
NCT02561091	PHASE3	COMPLETED	AM-111 in the Treatment of Acute Inner Ear Hearing Loss
NCT03331627	PHASE3	COMPLETED	Safety and Efficacy of STR001-IT and STR001-ER in Patients With SSHL
NCT05532657	PHASE3	ACTIVE_NOT_RECRUITING	ACHIEVE Brain Health Follow-Up Study
NCT00013455	PHASE2	COMPLETED	Quantifying Auditory Perceptual Learning Following Hearing Aid Fitting
NCT00323427	PHASE2	COMPLETED	Clinical Trial of the Living Well With Hearing Loss Workshop
NCT00552786	PHASE2	COMPLETED	Antioxidation Medication for Noise-induced Hearing Loss
NCT00802425	PHASE2	COMPLETED	Efficacy of AM-111 in Patients With Acute Sensorineural Hearing Loss
NCT01139281	PHASE2	COMPLETED	The Protective Effect of Ginkgo Biloba Extract on Cisplatin-induced Ototoxicity in Humans
NCT01451853	PHASE2	UNKNOWN	SPI-1005 for Prevention and Treatment of Chemotherapy Induced Hearing Loss
NCT01588925	PHASE2	COMPLETED	Hearing Preservation Using Dexamethasone and Hyaluronic Acid for Cochlear Implantation
NCT01773278	PHASE2	RECRUITING	Cholesterol and Antioxidant Treatment in Patients With Smith-Lemli-Opitz Syndrome (SLOS)
NCT02832128	PHASE2	COMPLETED	Evaluating Possible Improvement in Speech and Hearing Tests After 28 Days of Dosing of the Study Drug AUT00063 Compared to Placebo (QuicKfire)
NCT04915183	PHASE2	RECRUITING	Atorvastatin to Reduce Cisplatin-Induced Hearing Loss Among Individuals With Head and Neck Cancer
NCT05258773	PHASE2	COMPLETED	Evaluation of the Presence of SENS-401 in the Perilymph
NCT06340633	PHASE2	RECRUITING	SPI-1005 in Adults Receiving Cochlear Implant
NCT00582946	PHASE1	COMPLETED	Wide-Bandwidth Open Canal Hearing Aid For Better Multitalker Speech Understanding
NCT00584155	PHASE1	WITHDRAWN	Protection From Cisplatin Ototoxicity by Lactated Ringers
NCT01206829	PHASE1	UNKNOWN	Hearing Impairment, Cognitive Therapy and Coping
NCT01256229	PHASE1	COMPLETED	Outcomes In Children With Developmental Delay And Deafness
NCT01343394	PHASE1	WITHDRAWN	Safety of Autologous Human Umbilical Cord Blood Mononuclear Fraction to Treat Acquired Hearing Loss in Children
NCT01452607	PHASE1	COMPLETED	Study to Evaluate the Safety and Pharmacokinetics of SPI-1005
NCT02259595	PHASE1	COMPLETED	Study to Determine the Safety, Tolerability, and Pharmacokinetic Profile of HPN-07 and HPN-07 Plus NAC
NCT04041440	PHASE1	COMPLETED	Speech Recognition Training in Children With Hearing Loss
NCT07218913	PHASE1	RECRUITING	Testing the Addition of Pedmark to Cisplatin Chemotherapy for Reducing Drug-Induced Ear Damage in Men With Stage II-III Metastatic Testicular Germ Cell Tumors
NCT00486577	PHASE2/PHASE3	COMPLETED	Chronic Electrical Stimulation of the Auditory Cortex for Intractable Tinnitus
NCT00789061	PHASE2/PHASE3	UNKNOWN	Applying Proton Pump Inhibitor to Prevent and Treat Acute Fluctuating Hearing Loss in Patients With SLC26A4 Mutation
NCT01423409	PHASE2/PHASE3	COMPLETED	Multicenter Trial Assessing an Innovative VAS of Pain Among Deaf People
NCT05786378	PHASE2/PHASE3	UNKNOWN	Assessment of The Efficacy of Intratympanic Platelet Rich Plasma for Treatment of Sensorineural Hearing Loss.
NCT01108601	PHASE1/PHASE2	UNKNOWN	Transtympanic Ringer’s Lactate for the Prevention of Cisplatin Ototoxicity
NCT01621256	PHASE1/PHASE2	COMPLETED	Efficacy, Safety, and Tolerability of Ancrod in Patients With Sudden Hearing Loss
NCT06370351	PHASE1/PHASE2	RECRUITING	A Phase I/II Clinical Trial with SENS-501 in Children Suffering from Severe to Profound Hearing Loss Due to Otoferlin (OTOF) Mutations
NCT06545175	PHASE1/PHASE2	RECRUITING	Intracochlear Application of VSF1.01 for the Reduction of Cochlear Implant Surgery Related Trauma
NCT07304024	PHASE1/PHASE2	RECRUITING	A Treatment for a Form of Age-Related Central Auditory Processing Disorder Consisting of Clemastine Fumarate Plus Engineered Sound
NCT01109576	EARLY_PHASE1	COMPLETED	Workshops for Veterans With Vision and Hearing Loss