POLD4

Summary

POLD4 (DNA polymerase delta 4, accessory subunit, HGNC:14106) is a protein-coding gene on chromosome 11q13.2, encoding DNA polymerase delta subunit 4 (Q9HCU8). As a component of the tetrameric DNA polymerase delta complex (Pol-delta4), plays a role in high fidelity genome replication and repair.

This gene encodes the smallest 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 enhances the activity of DNA polymerase delta and plays a role in fork repair and stabilization through interactions with the DNA helicase Bloom syndrome protein. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene.

Source: NCBI Gene 57804 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 1 total
• GTEx eGene: eQTL in 12 tissues, sQTL in 3 (q < 0.05)
• Constraint (gnomAD): pLI 0.01 (LoF-tolerant), LOEUF 1.27 (unconstrained)
• MANE Select transcript: NM_021173

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14106
Approved symbol	POLD4
Name	DNA polymerase delta 4, accessory subunit
Location	11q13.2
Locus type	gene with protein product
Status	Approved
Aliases	p12, POLDS
Ensembl gene	ENSG00000175482
Ensembl biotype	protein_coding
OMIM	611525
Entrez	57804

Gene structure

Transcript identifiers

Ensembl transcripts: 20 — 14 protein_coding, 6 retained_intron

MANE Select: ENST00000312419

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 4, TSL 2: 4, TSL 3: 2, TSL 4: 1, TSL 5: 1

ENST00000312419, ENST00000524743, ENST00000528087, ENST00000529000, ENST00000529704, ENST00000530584, ENST00000531239, ENST00000532830, ENST00000533429, ENST00000534515, ENST00000539074, ENST00000542982, ENST00000944954, ENST00000990764, ENST00000990765, ENST00000990766, ENST00001083933, ENST00001083934, ENST00001126558, ENST00001135981

RefSeq mRNA: 2 — MANE Select: NM_021173 NM_001256870, NM_021173

CCDS: CCDS58149, CCDS8158

Canonical transcript exons

ENST00000312419 — 4 exons

Exon	Start	End
ENSE00001213808	67353303	67353546
ENSE00003655650	67352691	67352802
ENSE00003672983	67352988	67353077
ENSE00003841909	67350772	67352019

Expression profiles

Bgee: expression breadth ubiquitous, 138 present calls, max score 98.71.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 82.5918 / max 651.2332, expressed in 1826 samples.

Highest expression (Bgee): mucosa of transverse colon, lobe of liver, granulocyte, lower esophagus mucosa, duodenum.

Genetic regulation across tissues (GTEx eQTL / sQTL)

POLD4 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 12 tissues and its splicing (sQTL) in 3 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

15 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Testis	eqtl	1.1e-06	+0.48	11:67098281:C:T
Cells EBV-transformed lymphocytes	sqtl	3.6e-04	+0.61	11:67165282:C:A
Stomach	eqtl	1.2e-03	-0.23	11:67102410:T:A
Skin Not Sun Exposed Suprapubic	eqtl	4.5e-03	+0.14	11:67331152:C:T
Muscle Skeletal	eqtl	5.1e-03	+0.16	11:67368947:T:C
Brain Cerebellar Hemisphere	eqtl	1.1e-02	+0.78	11:67222961:G:A
Esophagus Mucosa	eqtl	1.3e-02	-0.21	11:67313828:G:C
Minor Salivary Gland	eqtl	2.5e-02	+0.31	11:67324862:A:ATTAT
Bladder	eqtl	2.7e-02	+2.61	11:66949878:A:C
Esophagus Muscularis	eqtl	3.6e-02	-0.43	11:67510947:G:A
Adipose Visceral Omentum	sqtl	4.5e-02	-1.24	11:67898523:C:A
Testis	sqtl	4.6e-02	-0.46	11:67716756:G:C
Artery Aorta	eqtl	4.7e-02	-0.40	11:67308996:C:T
Brain Nucleus accumbens basal ganglia	eqtl	4.7e-02	-0.79	11:67118885:G:C
Cells Cultured fibroblasts	eqtl	4.8e-02	+0.23	11:66873776:C:A

FANTOM5 promoters

6 alternative TSS:

Promoter ID	TPM avg	Samples expressed
120896	75.7631	1826
120895	6.2272	1321
120897	0.4080	209
120893	0.1140	42
120899	0.0457	19
120898	0.0338	9

Top tissues by expression

showing 100 of 138 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
mucosa of transverse colon	UBERON:0004991	98.71	gold quality
right lobe of liver	UBERON:0001114	97.71	gold quality
granulocyte	CL:0000094	97.70	gold quality
lower esophagus mucosa	UBERON:0035834	97.69	gold quality
duodenum	UBERON:0002114	97.58	gold quality
vermiform appendix	UBERON:0001154	97.31	gold quality
lymph node	UBERON:0000029	97.22	gold quality
descending thoracic aorta	UBERON:0002345	97.07	gold quality
blood	UBERON:0000178	97.06	gold quality
left coronary artery	UBERON:0001626	97.01	gold quality
small intestine Peyer’s patch	UBERON:0003454	97.01	gold quality
right coronary artery	UBERON:0001625	96.90	gold quality
small intestine	UBERON:0002108	96.87	gold quality
spleen	UBERON:0002106	96.81	gold quality
transverse colon	UBERON:0001157	96.76	gold quality
liver	UBERON:0002107	96.71	gold quality
thoracic aorta	UBERON:0001515	96.65	gold quality
ascending aorta	UBERON:0001496	96.61	gold quality
body of pancreas	UBERON:0001150	96.58	gold quality
popliteal artery	UBERON:0002250	96.55	gold quality
tibial artery	UBERON:0007610	96.55	gold quality
leukocyte	CL:0000738	96.49	gold quality
monocyte	CL:0000576	96.41	gold quality
esophagus mucosa	UBERON:0002469	96.38	gold quality
body of stomach	UBERON:0001161	96.09	gold quality
right atrium auricular region	UBERON:0006631	95.99	gold quality
adult mammalian kidney	UBERON:0000082	95.74	gold quality
mucosa of stomach	UBERON:0001199	95.71	gold quality
prostate gland	UBERON:0002367	95.68	gold quality
esophagus	UBERON:0001043	95.55	gold quality
apex of heart	UBERON:0002098	95.39	gold quality
right adrenal gland	UBERON:0001233	95.24	gold quality
minor salivary gland	UBERON:0001830	95.22	gold quality
saliva-secreting gland	UBERON:0001044	95.21	gold quality
omental fat pad	UBERON:0010414	95.17	gold quality
colon	UBERON:0001155	95.11	gold quality
vagina	UBERON:0000996	95.06	gold quality
intestine	UBERON:0000160	95.05	gold quality
left adrenal gland	UBERON:0001234	95.00	gold quality
right lung	UBERON:0002167	94.97	gold quality
adipose tissue	UBERON:0001013	94.94	gold quality
bone marrow cell	CL:0002092	94.93	gold quality
lower esophagus	UBERON:0013473	94.92	gold quality
lower esophagus muscularis layer	UBERON:0035833	94.92	gold quality
fundus of stomach	UBERON:0001160	94.90	gold quality
heart left ventricle	UBERON:0002084	94.90	gold quality
right adrenal gland cortex	UBERON:0035827	94.88	gold quality
subcutaneous adipose tissue	UBERON:0002190	94.81	gold quality
left adrenal gland cortex	UBERON:0035825	94.74	gold quality
heart	UBERON:0000948	94.53	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	94.49	gold quality
gastrocnemius	UBERON:0001388	94.46	gold quality
stomach	UBERON:0000945	94.42	gold quality
myometrium	UBERON:0001296	94.27	gold quality
upper lobe of left lung	UBERON:0008952	94.14	gold quality
urinary bladder	UBERON:0001255	94.03	gold quality
muscle of leg	UBERON:0001383	94.01	gold quality
tibial nerve	UBERON:0001323	93.95	gold quality
metanephros cortex	UBERON:0010533	93.93	gold quality
cortex of kidney	UBERON:0001225	93.79	gold quality
tonsil	UBERON:0002372	93.72	gold quality
thoracic mammary gland	UBERON:0005200	93.58	gold quality
ectocervix	UBERON:0012249	93.55	gold quality
adrenal gland	UBERON:0002369	93.48	gold quality
muscle layer of sigmoid colon	UBERON:0035805	93.35	gold quality
right lobe of thyroid gland	UBERON:0001119	93.34	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	93.26	gold quality
left uterine tube	UBERON:0001303	93.17	gold quality
bone marrow	UBERON:0002371	93.14	gold quality
endocervix	UBERON:0000458	93.12	gold quality
uterine cervix	UBERON:0000002	93.11	gold quality
hindlimb stylopod muscle	UBERON:0004252	93.08	gold quality
body of uterus	UBERON:0009853	92.84	gold quality
kidney	UBERON:0002113	92.69	gold quality
anatomical system	UBERON:0000467	92.62	gold quality
material anatomical entity	UBERON:0000465	92.59	gold quality
multicellular organism	UBERON:0000468	92.59	gold quality
left lobe of thyroid gland	UBERON:0001120	92.55	gold quality
stromal cell of endometrium	CL:0002255	92.39	gold quality
skin of abdomen	UBERON:0001416	92.38	gold quality
skin of leg	UBERON:0001511	92.35	gold quality
left ovary	UBERON:0002119	92.34	gold quality
zone of skin	UBERON:0000014	92.27	gold quality
skeletal muscle tissue	UBERON:0001134	92.20	gold quality
right ovary	UBERON:0002118	92.16	gold quality
thyroid gland	UBERON:0002046	92.14	gold quality
placenta	UBERON:0001987	92.08	gold quality
gall bladder	UBERON:0002110	92.02	gold quality
adenohypophysis	UBERON:0002196	92.01	gold quality
pancreas	UBERON:0001264	91.90	gold quality
lung	UBERON:0002048	91.81	gold quality
ovary	UBERON:0000992	91.67	gold quality
pituitary gland	UBERON:0000007	91.48	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	91.31	gold quality
colonic epithelium	UBERON:0000397	90.79	gold quality
muscle tissue	UBERON:0002385	90.75	gold quality
substantia nigra	UBERON:0002038	90.66	gold quality
rectum	UBERON:0001052	89.96	gold quality
sural nerve	UBERON:0015488	89.94	gold quality
putamen	UBERON:0001874	88.85	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-CURD-114	yes	57.16
E-CURD-122	yes	18.76
E-ANND-3	no	0.00

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 76 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM
Small intestine	tissue	88.3
Duodenum	tissue	80.9
Lymph node	tissue	77.8
Stomach 1	tissue	65.6
Appendix	tissue	57.0
Vagina	tissue	53.9
Liver	tissue	51.1
Colon	tissue	48.8
Skeletal muscle	tissue	47.2
Salivary gland	tissue	40.5
Pancreas	tissue	39.1
Spleen	tissue	38.9
Bone marrow	tissue	35.0
Adipose tissue	tissue	27.6
Heart muscle	tissue	27.3
Pituitary gland	tissue	27.2
Locus coeruleus	tissue	25.6
Prostate	tissue	23.8
Tonsil	tissue	23.8
Adrenal gland	tissue	23.5
Choroid plexus	tissue	23.4
Kidney	tissue	23.2
Frontal cortex	tissue	22.5
Hippocampus	tissue	20.6
Lung	tissue	19.8
Postcentral gyrus	tissue	19.2
Nucleus accumbens	tissue	18.4
Caudate putamen	tissue	18.4
Gallbladder	tissue	18.0
Placenta	tissue	16.2
Spinal cord	tissue	16.2
Substantia nigra	tissue	14.2
Corpus callosum	tissue	14.0
Rectum	tissue	13.9
Ovary	tissue	13.7
Medulla oblongata	tissue	13.7
Superior colliculi	tissue	13.7
Pons	tissue	13.2
Esophagus	tissue	12.7
Hypothalamus	tissue	12.7
Midbrain	tissue	12.5
Thalamus	tissue	12.2
Urinary bladder	tissue	12.0
Periaqueductal gray	tissue	11.9
Endometrium 1	tissue	11.8
Skin 1	tissue	10.6
Septum	tissue	10.6
Putamen	tissue	10.3
Ventral forebrain	tissue	10.0
Olfactory bulb	tissue	9.3
Smooth muscle	tissue	9.2
Amygdala	tissue	9.2
Seminal vesicle	tissue	9.0
Thyroid gland	tissue	8.9
Hippocampal formation	tissue	8.9
Cerebral cortex	tissue	8.8
Basal ganglia	tissue	8.8
Insular cortex	tissue	8.8
Tongue	tissue	8.6
Motor cortex	tissue	8.5

Brain sub-regions (HPA Brain Atlas): detected in 189; highest nTPM — Blood vessel (91.8), Area postrema (28.6), Anterior thalamic nucleus, ventral (28.2), Dorsal tegmental nucleus (27.1), Median raphe nucleus (26.7).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting POLD4 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

30 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-6798-5P	100.00	65.77	699
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-613	99.91	71.50	1710
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-6716-5P	99.56	68.62	1244
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-6727-3P	99.49	65.92	1333
HSA-MIR-504-3P	99.30	67.18	1745
HSA-MIR-133A-5P	99.28	69.13	941
HSA-MIR-544B	99.18	67.41	1632
HSA-MIR-4270	99.02	66.26	1987
HSA-MIR-4763-5P	98.75	63.89	854
HSA-MIR-4635	98.74	67.63	1339
HSA-MIR-3161	98.71	67.14	816
HSA-MIR-6754-5P	98.60	65.54	1627
HSA-MIR-5589-5P	98.34	64.82	1148
HSA-MIR-340-3P	98.11	68.25	679
HSA-MIR-4483	98.09	64.12	1642
HSA-MIR-6827-3P	98.08	72.27	651
HSA-MIR-596	97.48	63.13	469
HSA-MIR-3169	96.40	67.58	698
HSA-MIR-4749-3P	96.40	66.24	798
HSA-MIR-4529-3P	96.40	66.46	582
HSA-MIR-3918	96.13	64.65	1300

Functional genomics

gnomAD constraint: pLI 0.00683, LOEUF 1.27, missense Z -0.0976 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000312419 — one region, missense o/e 0.92.

Literature-anchored findings (GeneRIF, showing 15)

• pol delta interacts with PCNA via at least two of its subunits, and p12 could play a role in stabilizing the overall pol delta-PCNA complex as well as pol delta itself (PMID:16510448)
• The DNA polymerase delta enzyme, as well as the isolated p12 subunit, stimulates the DNA helicase activity of Bloom’s syndrome helicase. (PMID:18682526)
• these results indicate that POLD4 is required for the in vitro pol delta activity, and that it functions in cell proliferation and maintenance of genomic stability of human cells. (PMID:19931513)
• Low POLD4 is associated with lung cancer. (PMID:20861182)
• The identification of RNF8 allows new insights into the integration of the control of p12 degradation by different DNA damage signaling pathways. (PMID:23233665)
• Data indicate that CRL4(Cdt2) regulates the degradation of the p12 subunit of Pol delta4. (PMID:23913683)
• ubiquitination of p12 through CRL4(Cdt2) and subsequent degradation form one mechanism by which a cell responds to DNA damage to inhibit fork progression. (PMID:24022480)
• 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)
• A parallel study of Pol delta4 and Pol delta3 in Okazaki fragment processing provides evidence for a role of Pol delta3 in DNA replication (PMID:24300032)
• the p12/Pol delta is a target as a nuclear substrate of mu-calpain in a calcium-triggered apoptosis and appears to be a potential marker in the study of the chemotherapy of cancer therapies. (PMID:24691096)
• Human Poldelta is a pentameric complex with a dimeric p12 subunit. RKR-mediated dimerization plays a vital role in p12 binding to PCNA and Poldelta5 architecture, and the phenomenon appears to be conserved throughout evolution. (PMID:30885984)
• The role in cellular processes (DNA replication, DNA repair, homologous recombination) and cell cycle regulation of 2 forms of human DNA polymerase delta: delta3 and delta4 was reviewed. (REVIEW) (PMID:31326365)
• Circular RNA circ_0026359 Enhances Cisplatin Resistance in Gastric Cancer via Targeting miR-1200/POLD4 Pathway. (PMID:32855967)
• Expression Profile, Molecular Association, and Clinical Significance of POLD4 in Glioblastoma. (PMID:37543966)
• POLD4 Promotes Glioma Cell Proliferation and Suppressive Immune Microenvironment: A Pan-Cancer Analysis Integrated with Experimental Validation. (PMID:37762224)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	pold4	ENSDARG00000079632
mus_musculus	Pold4	ENSMUSG00000024854
rattus_norvegicus	Pold4	ENSRNOG00000018765

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1916995) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 4 distinct phenotype terms.

Mouse phenotype (MP)	Records
decreased circulating calcium level	1
decreased leukocyte cell number	1
extended life span	1
decreased liver tumor incidence	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Bos taurus	Q3T0X9	86.0%	Diamond
Schizosaccharomyces pombe 972h-	O59835	46.3%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
CLCF1	protein-coding	23529
ANKRD13D	protein-coding	338692
SSH3	protein-coding	54961
PPP1CA	protein-coding	5499
RAD9A	protein-coding	5883
GRK2	protein-coding	156
KDM2A	protein-coding	22992

Protein

Protein identifiers

DNA polymerase delta subunit 4 — Q9HCU8 (reviewed: Q9HCU8)

Alternative names: DNA polymerase delta subunit p12

All UniProt accessions (2): E9PL15, Q9HCU8

UniProt curated annotations — full annotation on UniProt →

Function. As a component of the tetrameric DNA polymerase delta complex (Pol-delta4), plays a role in high fidelity genome replication and repair. Within this complex, increases the rate of DNA synthesis and decreases fidelity by regulating POLD1 polymerase and proofreading 3’ to 5’ exonuclease activity. Pol-delta4 participates in Okazaki fragment processing, through both the short flap pathway, as well as a nick translation system. Under conditions of DNA replication stress, required for the repair of broken replication forks through break-induced replication (BIR), a mechanism that may induce segmental genomic duplications of up to 200 kb. Involved in Pol-delta4 translesion synthesis (TLS) of templates carrying O6-methylguanine or abasic sites. Its degradation in response to DNA damage is required for the inhibition of fork progression and cell survival.

Subunit / interactions. Component of 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 POLD1 and POLD2. Directly interacts with PCNA, as do POLD1 and POLD3; this interaction stimulates Pol-delta4 polymerase activity. As POLD1 and POLD2, directly interacts with WRNIP1; this interaction stimulates DNA polymerase delta-mediated DNA synthesis, independently of the presence of PCNA. This stimulation may be due predominantly to an increase of initiation frequency and also to increased processivity. Upon genotoxic stress induced by DNA damaging agents or by replication stress, POLD4 is proteolytically degraded and Pol-delta4 is converted into a trimeric form of the complex (Pol-delta3) which has an increased proofreading activity. The DNA polymerase delta complex interacts with POLDIP2; this interaction is probably mediated through direct binding to POLD2.

Subcellular location. Nucleus.

Post-translational modifications. Ubiquitinated; undergoes ‘Lys-48’-linked ubiquitination in response to UV irradiation, leading to proteasomal degradation. This modification is partly mediated by RNF8 and by the DCX(DTL) E3 ubiquitin ligase complex (also called CRL4(CDT2)). Efficient degradation requires the presence of PCNA and is required for the inhibition of fork progression after DNA damage.

Induction. In response to DNA damage, genotoxic stress and replication stress, following UV irradiation, ionizing radiation, treatment with methyl methanesulfonate, hydroxyurea, or with aphidicolin, protein expression drops to undetectable levels, due to proteasomal degradation. This down-regulation is ATR-dependent.

Similarity. Belongs to the DNA polymerase delta subunit 4 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9HCU8-1	1	yes
Q9HCU8-2	2

RefSeq proteins (2): NP_001243799, NP_066996* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007218	DNA_pol_delta_4	Family

Pfam: PF04081

UniProt features (31 total): mutagenesis site 17, helix 3, strand 3, sequence variant 2, chain 1, region of interest 1, short sequence motif 1, turn 1, compositionally biased region 1, splice variant 1

Structure

Experimental structures (PDB)

7 structures by resolution:

PDB	Title	Method	Resolution (Å)
6HVO	Crystal structure of human PCNA in complex with three peptides of p12 subunit of human …	X-RAY DIFFRACTION	2.1
6TNY	Processive human polymerase delta holoenzyme	ELECTRON MICROSCOPY	3.08
9EKB	Cryo-EM structure of apo-form human DNA polymerase delta	ELECTRON MICROSCOPY	3.65
6TNZ	Human polymerase delta-FEN1-PCNA toolbelt	ELECTRON MICROSCOPY	4.05
6S1M	Human polymerase delta holoenzyme Conformer 1	ELECTRON MICROSCOPY	4.27
6S1N	Human polymerase delta holoenzyme Conformer 2	ELECTRON MICROSCOPY	4.86
6S1O	Human polymerase delta holoenzyme Conformer 3	ELECTRON MICROSCOPY	8.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9HCU8-F1	85.73	0.63

Human Protein Atlas

Protein class: Metabolic proteins, Predicted intracellular proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): centriolar satellite

Antibody reliability (HPA): IF approved

Functional residue map

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

Mutagenesis-validated functional residues (17)

Position	Phenotype
4	no effect on ubiquitination. loss of ubiquitination, when associated with r-15, r-25, r-74 and r-89.
7	complete loss of pcna binding; when associated with 10-aa-11.
8	strongly increased stability following uv irradiation; when associated with a-9.
8	complete loss of pcna binding.
9	strongly increased stability following uv irradiation; when associated with a-8.
10–11	complete loss of pcna binding; when associated with a-7.
10	no effect on pcna binding, nor on degradation after uv irradiation; when associated with q-4. no effect on pcna binding, but normal …
15	decreased pcna binding. no effect on pcna binding, but normal degradation after uv irradiation; when associated with q-4 and y-10 …
15	no effect on ubiquitination. loss of ubiquitination; when associated with r-4, r-25, r-74 and r-89.
16	increased stability following uv irradiation and no trough during s phase; when associated with a-15 and a-17.
17	increased stability following uv irradiation and no trough during s phase; when associated with a-15 and a-16.
25	no effect on ubiquitination. loss of ubiquitination; when associated with r-4, r-15, r-74 and r-89.
74	no effect on ubiquitination. loss of ubiquitination; when associated with r-4, r-15, r-25 and r-89.
89	no effect on ubiquitination. loss of ubiquitination; when associated with r-4, r-15, r-25 and r-74.
1–16	complete loss of pcna binding and of degradation after uv irradiation.
4	no effect on pcna binding.
4	no effect on pcna binding, nor on degradation after uv irradiation; when associated with y-10. no effect on pcna binding, but normal …

Function

Pathways and Gene Ontology

Reactome pathways

17 curated (TAS) of 41; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

41 pathways:

ID	Pathway	Evidence
R-HSA-5696400	Dual Incision in GG-NER	curated
R-HSA-6782135	Dual incision in TC-NER	curated
R-HSA-5696397	Gap-filling DNA repair synthesis and ligation in GG-NER	curated
R-HSA-6782210	Gap-filling DNA repair synthesis and ligation in TC-NER	curated
R-HSA-5685942	HDR through Homologous Recombination (HRR)	curated
R-HSA-5358606	Mismatch repair (MMR) directed by MSH2:MSH3 (MutSbeta)	curated
R-HSA-5358565	Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha)	curated
R-HSA-5651801	PCNA-Dependent Long Patch Base Excision Repair	curated
R-HSA-69091	Polymerase switching	curated
R-HSA-174411	Polymerase switching on the C-strand of the telomere	curated
R-HSA-174414	Processive synthesis on the C-strand of the telomere	curated
R-HSA-69183	Processive synthesis on the lagging strand	curated
R-HSA-110314	Recognition of DNA damage by PCNA-containing replication complex	curated
R-HSA-69166	Removal of the Flap Intermediate	curated
R-HSA-174437	Removal of the Flap Intermediate from the C-strand	curated
R-HSA-174417	Telomere C-strand (Lagging Strand) Synthesis	curated
R-HSA-5656169	Termination of translesion DNA synthesis	curated
R-HSA-73884	Base Excision Repair	—
R-HSA-1640170	Cell Cycle	—
R-HSA-69278	Cell Cycle, Mitotic	—
R-HSA-73886	Chromosome Maintenance	—
R-HSA-73893	DNA Damage Bypass	—
R-HSA-5693532	DNA Double-Strand Break Repair	—
R-HSA-73894	DNA Repair	—
R-HSA-69306	DNA Replication	—
R-HSA-69190	DNA strand elongation	—
R-HSA-180786	Extension of Telomeres	—
R-HSA-5696399	Global Genome Nucleotide Excision Repair (GG-NER)	—
R-HSA-5693567	HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	—
R-HSA-5693538	Homology Directed Repair	—
R-HSA-69186	Lagging Strand Synthesis	—
R-HSA-69109	Leading Strand Synthesis	—
R-HSA-5358508	Mismatch Repair	—
R-HSA-5696398	Nucleotide Excision Repair	—
R-HSA-110373	Resolution of AP sites via the multiple-nucleotide patch replacement pathway	—
R-HSA-73933	Resolution of Abasic Sites (AP sites)	—
R-HSA-69242	S Phase	—
R-HSA-69239	Synthesis of DNA	—
R-HSA-157579	Telomere Maintenance	—
R-HSA-6781827	Transcription-Coupled Nucleotide Excision Repair (TC-NER)	—
R-HSA-110313	Translesion synthesis by Y family DNA polymerases bypasses lesions on DNA template	—

MSigDB gene sets: 275 (showing top): REACTOME_DNA_REPLICATION, AP1_01, LFA1_Q6, ENK_UV_RESPONSE_KERATINOCYTE_UP, GCANCTGNY_MYOD_Q6, KAAB_HEART_ATRIUM_VS_VENTRICLE_UP, TGACCTY_ERR1_Q2, AP2_Q3, KAUFFMANN_DNA_REPAIR_GENES, GGGTGGRR_PAX4_03, chr11q13, CAGCTG_AP4_Q5, KEGG_HOMOLOGOUS_RECOMBINATION, GOCC_NUCLEAR_REPLICATION_FORK, MISSIAGLIA_REGULATED_BY_METHYLATION_UP

GO Biological Process (5): DNA synthesis involved in DNA repair (GO:0000731), DNA-templated DNA replication (GO:0006261), DNA replication (GO:0006260), DNA repair (GO:0006281), DNA damage response (GO:0006974)

GO Molecular Function (2): DNA-directed DNA polymerase activity (GO:0003887), protein binding (GO:0005515)

GO Cellular Component (3): nucleoplasm (GO:0005654), delta DNA polymerase complex (GO:0043625), nucleus (GO:0005634)

Reactome top-level categories

15 top-level categories:

Category	Pathways
DNA Damage Bypass	2
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
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
Resolution of Abasic Sites (AP sites)	1
Chromosome Maintenance	1

GO top-level categories

14 GO namespaces:

Category	Terms
DNA biosynthetic process	2
DNA metabolic process	2
DNA repair	1
DNA replication	1
DNA damage response	1
cellular response to stress	1
DNA polymerase activity	1
binding	1
nuclear lumen	1
cellular anatomical structure	1
DNA polymerase complex	1
nuclear replisome	1
nuclear protein-containing complex	1
intracellular membrane-bounded organelle	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 1 of 10 annotations. The rest are phylogenetic / computational / electronic (IEA).

1 experimentally-supported GO terms:

GO term	NS	Evidence
DNA-templated DNA replication	BP	direct assay

Protein interactions and networks

STRING

showing 15 of 341 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
POLD4	POLD3	Q15054	954
POLD4	POLD1	P28340	896
POLD4	POLD2	P49005	862
POLD4	LIG1	P18858	738
POLD4	PCNA	P12004	632
POLD4	TTC9C	Q8N5M4	441
POLD4	SUMO2	P55855	427
POLD4	ANKRD13D	Q6ZTN6	419
POLD4	ATM	Q13315	376
POLD4	C11orf24	Q96F05	360
POLD4	EFCC1	Q9HA90	340
POLD4	TMEM109	Q9BVC6	323
POLD4	ZBTB3	Q9H5J0	323
POLD4	POLE2	P56282	315
POLD4	PDXDC1	Q6P996	315

IntAct

Human interaction partners of POLD4 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

4 partners by confidence:

Partner	Interaction type	MIscore	Records
POLD1	physical association	0.900	8
POLD2	physical association	0.790	3
PCNA	physical association	0.520	4
WRNIP1	physical association	0.500	1

BioGRID (18 interactions; top human partners by supporting records): POLD1 (Affinity Capture-MS; 4 records), POLD2 (Affinity Capture-MS; 4 records), PCNA (Reconstituted Complex; 3 records), BRD4 (Affinity Capture-MS), DTL (Biochemical Activity), POLD3 (Reconstituted Complex), POLE (Reconstituted Complex), POLE2 (Co-fractionation), RNF8 (Biochemical Activity), SPRTN (Affinity Capture-MS)

SIGNOR signaling

1 signaling interactions:

A	Effect	B	Mechanism
POLD4	“form complex”	“DNA polymerase delta”	binding

Protein complexes (CORUM) (7)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

7 complexes by size:

Complex	Subunits	Members
★ RC complex, S-phase-specific	23	POLD4, POLE2, POLE4, CCNA2, CDK2, POLD2, POLD3, RFC2, POLE, RFC1, RFC5, RPA3, LIG1, PARP1, POLA1, POLD1, RFC3, RPA2, POLA2, POLE3, RFC4, RPA1, TOP1
★ DNA synthesome complex, breast cancer MCF7 cells	23	POLA2, POLD3, POLE4, PRIM1, RFC1, RPA1, PCNA, POLD4, POLE2, POLE3, RFC4, TOP1, POLA1, RFC2, RFC3, RFC5, RPA2, RPA3, TOP2A, POLD1, POLD2, POLE, PRIM2
★ DNA synthesome complex, breast cancer cells	20	POLD3, POLE4, RFC2, RFC3, POLA2, POLE3, LIG1, PARP1, PCNA, POLD2, PRIM1, PRIM2, RFC1, RFC4, POLD4, POLE, POLE2, RFC5, POLA1, POLD1
★ RC complex, G2/M-phase-specific	19	CCNB1, POLA1, POLA2, POLD2, RPA1, RPA2, CDK1, POLD3, RFC1, RFC2, RPA3, POLD1, POLD4, POLE, POLE3, PARP1, POLE2, POLE4, TOP1
★ DNA synthesome complex, leukemia cells	19	PCNA, POLD1, RFC5, TOP2A, POLD4, PRIM1, PRIM2, RFC2, RPA2, TOP1, POLD2, POLD3, RPA1, POLA1, POLA2, RFC1, RFC3, RFC4, RPA3
★ DNA synthesome core complex	14	PCNA, POLA2, POLD1, POLD2, POLD3, POLD4, PRIM2, RFC1, POLA1, PRIM1, RFC2, RFC3, RFC4, RFC5
★ DNA polymerase delta	4	POLD1, POLD2, POLD3, POLD4

Disease & clinical

Genetic variants

Variant evidence for POLD4: 1 ClinVar records (0 pathogenic / likely pathogenic); 5 GWAS associations.

ClinVar

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

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

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 15 predictions of 340):

Position(s)	Effect	Δscore	Sites
11:67352890	donor_gain	1.0000
11:67353306	donor_gain	1.0000
11:67353348	donor_gain	1.0000
11:67352053	acceptor_gain	0.9900
11:67353322	donor_gain	0.9900
11:67352054	acceptor_gain	0.9800
11:67352833	acceptor_gain	0.9800
11:67352020–67352021	acceptor_loss	0.9700	6
11:67352022	acceptor_gain	0.9700
11:67353285	donor_gain	0.9700

AlphaMissense

156 missense substitutions predicted likely pathogenic (of 683 scored), across 41 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
D53	8	0.968	0.984
F52	8	0.939	0.993
W102	7	0.923	0.976
W70	7	0.883	0.966
C61	7	0.764	0.956
G59	6	0.958	0.984
G63	6	0.908	0.950
R69	6	0.886	0.985
P60	6	0.871	0.933
P80	6	0.825	0.955
R66	5	0.892	0.953
Y58	5	0.877	0.930
S100	5	0.850	0.905
L49	5	0.804	0.941
R72	5	0.799	0.964
A73	4	0.917	0.971
F97	4	0.847	0.874
Y11	4	0.785	0.865
M76	4	0.679	0.699
V84	4	0.670	0.858

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Disease associations

OMIM: gene MIM:611525 | disease phenotypes:

GWAS associations

5 associations:

Study	Trait	p-value
GCST007294_121	Body fat distribution (trunk fat ratio)	1e-35
GCST007294_155	Body fat distribution (trunk fat ratio)	8e-28
GCST007295_118	Body fat distribution (leg fat ratio)	1e-25
GCST007295_76	Body fat distribution (leg fat ratio)	1e-21
GCST007293_83	Body fat distribution (arm fat ratio)	9e-8

EFO canonical traits (from GWAS)

1 canonical traits:

EFO ID	Trait name
EFO:0004341	body fat distribution

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2363042 (PROTEIN FAMILY), CHEMBL4742319 (PROTEIN-PROTEIN INTERACTION)

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects expression, increases expression	4
Tretinoin	increases expression	3
Cyclosporine	decreases expression, decreases methylation, increases expression	3
Estradiol	decreases expression	2
Tetrachlorodibenzodioxin	increases expression	2
Aflatoxin B1	increases expression	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
afuresertib	increases expression	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
bisphenol A	decreases expression	1
beta-lapachone	increases expression	1
arsenite	affects binding, increases reaction	1
cobaltous chloride	decreases expression	1
tamibarotene	increases expression	1
di-n-butylphosphoric acid	affects expression	1
CPG-oligonucleotide	decreases expression	1
K 7174	increases expression	1
trans-10,cis-12-conjugated linoleic acid	increases expression	1
abrine	increases expression	1
Temozolomide	decreases expression	1
Arsenic Trioxide	increases expression	1
Acetaldehyde	decreases expression	1
Air Pollutants	affects expression, increases abundance	1
Arsenic	increases methylation	1
Azathioprine	increases expression	1
Cadmium	increases abundance, increases expression	1
Chlorpromazine	increases expression	1
Diazinon	increases methylation	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
CHEMBL4713781	Binding	Protac activity at CRBN/POLD4 in human BxPC-3 cells assessed as POLD4 degradation incubated for 16 hrs by proteomic analysis	Discovery of a Napabucasin PROTAC as an Effective Degrader of the E3 Ligase ZFP91. — *J Med Chem*

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.