POLD2

Summary

POLD2 (DNA polymerase delta 2, accessory subunit, HGNC:9176) is a protein-coding gene on chromosome 7p13, encoding DNA polymerase delta subunit 2 (P49005). Accessory component of both the DNA polymerase delta complex and the DNA polymerase zeta complex. It is a common-essential gene (DepMap: required in 97.7% of cancer cell lines).

This gene encodes the 50-kDa catalytic 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 is required for the stimulation of DNA polymerase delta activity by the processivity cofactor proliferating cell nuclear antigen (PCNA). Expression of this gene may be a marker for ovarian carcinomas. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene, and a pseudogene of this gene is located on the long arm of chromosome 5.

Source: NCBI Gene 5425 — RefSeq curated summary.

At a glance

• Gene–disease (curated): non-severe combined immunodeficiency due to polymerase delta deficiency (Moderate, GenCC)
• Clinical variants (ClinVar): 401 total (top 8% of genes corpus-wide)
• Regional missense constraint (gnomAD): 1 of 3 regions constrained (≈6% of expected missense variation)
• GTEx eGene: eQTL in 47 tissues, sQTL in 46 (q < 0.05)
• Cancer dependency (DepMap): dependent in 97.7% of screened cell lines (common-essential)
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.93 (unconstrained)
• MANE Select transcript: NM_006230
• Notable: 401 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9176
Approved symbol	POLD2
Name	DNA polymerase delta 2, accessory subunit
Location	7p13
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000106628
Ensembl biotype	protein_coding
OMIM	600815
Entrez	5425

Gene structure

Transcript identifiers

Ensembl transcripts: 151 — 77 protein_coding, 38 retained_intron, 34 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

MANE Select: ENST00000610533

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 2, TSL 2: 6, TSL 3: 6, TSL 4: 1, TSL 5: 3

ENST00000610533, ENST00000223361, ENST00000406581, ENST00000418438, ENST00000433715, ENST00000436400, ENST00000436844, ENST00000452185, ENST00000456038, ENST00000461116, ENST00000463464, ENST00000464871, ENST00000467469, ENST00000470867, ENST00000481104, ENST00000481763, ENST00000489883, ENST00000496539, ENST00000698945, ENST00000698946, ENST00000698947, ENST00000698948, ENST00000698949, ENST00000698950, ENST00000698951, ENST00000698952, ENST00000698953, ENST00000698954, ENST00000698955, ENST00000698956, ENST00000698957, ENST00000698958, ENST00000698959, ENST00000698960, ENST00000698961, ENST00000698962, ENST00000698963, ENST00000698964, ENST00000698965, ENST00000698966, ENST00000698967, ENST00000698968, ENST00000698969, ENST00000698970, ENST00000698971, ENST00000698972, ENST00000698973, ENST00000698974, ENST00000698975, ENST00000698976, ENST00000698977, ENST00000698978, ENST00000698979, ENST00000698980, ENST00000698981, ENST00000698982, ENST00000698983, ENST00000698984, ENST00000698985, ENST00000698986, ENST00000698987, ENST00000698988, ENST00000698989, ENST00000698990, ENST00000698991, ENST00000698992, ENST00000698993, ENST00000698994, ENST00000881299, ENST00000881300, ENST00000881301, ENST00000881302, ENST00000881303, ENST00000881304, ENST00000881305, ENST00000881306, ENST00000881307, ENST00000881308, ENST00000881309, ENST00000881310, ENST00000881311, ENST00000881312, ENST00000881313, ENST00000881314, ENST00000881315, ENST00000881316, ENST00000881317, ENST00000881318, ENST00000881319, ENST00000881320, ENST00000881321, ENST00000881322, ENST00000881323, ENST00000931682, ENST00000931683, ENST00000931684, ENST00000931685, ENST00000931686, ENST00000931687, ENST00000931688, ENST00000964228, ENST00000964229, ENST00000964230, ENST00000964231, ENST00000964232, ENST00000964233, ENST00000964234, ENST00000964235, ENST00000964236, ENST00000964237, ENST00000964238, ENST00001001123, ENST00001001124, ENST00001001126, ENST00001001128, ENST00001001130, ENST00001001131, ENST00001001132, ENST00001001133, ENST00001001134, ENST00001022268, ENST00001022269, ENST00001022270, ENST00001022273, ENST00001022274, ENST00001022275, ENST00001022276, ENST00001063687, ENST00001063688, ENST00001063689, ENST00001063690, ENST00001063691, ENST00001063692, ENST00001063693, ENST00001063694, ENST00001063695, ENST00001101575, ENST00001101576, ENST00001101577, ENST00001101578, ENST00001101579, ENST00001101580, ENST00001101581, ENST00001101582, ENST00001101583, ENST00001101584, ENST00001101585, ENST00001101586, ENST00001101587, ENST00001110802, ENST00001141271

RefSeq mRNA: 3 — MANE Select: NM_006230 NM_001127218, NM_001256879, NM_006230

CCDS: CCDS5477

Canonical transcript exons

ENST00000610533 — 11 exons

Exon	Start	End
ENSE00000680769	44116430	44116510
ENSE00000680772	44116817	44117015
ENSE00000680774	44117133	44117247
ENSE00001761884	44116115	44116272
ENSE00003557682	44121834	44122109
ENSE00003727843	44123511	44123548
ENSE00003730786	44114680	44114945
ENSE00003975291	44115766	44115893
ENSE00003975308	44115295	44115396
ENSE00003975316	44117619	44117742
ENSE00003975338	44117943	44118064

Expression profiles

Bgee: expression breadth ubiquitous, 296 present calls, max score 97.31.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 20.4872 / max 130.8352, expressed in 1777 samples.

Highest expression (Bgee): uterine tube, apex of heart, ventricular zone, lobe of liver, lower esophagus mucosa.

Genetic regulation across tissues (GTEx eQTL / sQTL)

POLD2 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 47 tissues and its splicing (sQTL) in 46 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 93 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Cells Cultured fibroblasts	sqtl	1.1e-50	-0.93	7:44122210:A:G
Esophagus Mucosa	sqtl	9.7e-34	-0.85	7:44122210:A:G
Nerve Tibial	eqtl	3.4e-31	-1.10	7:44112387:G:A
Skin Sun Exposed Lower leg	eqtl	1.1e-28	-0.90	7:44112387:G:A
Skin Sun Exposed Lower leg	sqtl	2.1e-28	-0.75	7:44118226:T:C
Muscle Skeletal	sqtl	7.3e-28	-0.61	7:44122210:A:G
Esophagus Muscularis	sqtl	1.2e-27	-0.80	7:44129790:G:C
Thyroid	eqtl	1.3e-27	-1.11	7:44112387:G:A
Brain Frontal Cortex BA9	eqtl	1.4e-27	-1.64	7:44112387:G:A
Thyroid	sqtl	2.9e-27	-0.72	7:44122210:A:G
Skin Not Sun Exposed Suprapubic	eqtl	2.7e-26	-1.01	7:44112387:G:A
Cells Cultured fibroblasts	eqtl	5.0e-26	-0.70	7:44112387:G:A
Muscle Skeletal	eqtl	1.1e-25	-1.16	7:44112387:G:A
Artery Tibial	sqtl	1.9e-24	-0.71	7:44129790:G:C
Nerve Tibial	sqtl	2.4e-24	-0.75	7:44122210:A:G
Skin Not Sun Exposed Suprapubic	sqtl	3.1e-23	-0.72	7:44112950:G:A
Lung	eqtl	3.9e-23	-0.84	7:44112387:G:A
Esophagus Muscularis	eqtl	4.1e-22	-1.36	7:44112387:G:A
Cells EBV-transformed lymphocytes	eqtl	6.7e-22	-0.93	7:44112387:G:A
Cells EBV-transformed lymphocytes	sqtl	3.4e-21	-0.88	7:44129790:G:C

FANTOM5 promoters

2 alternative TSS:

Promoter ID	TPM avg	Samples expressed
83847	19.6425	1775
83845	0.8447	565

Top tissues by expression

showing 100 of 301 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right uterine tube	UBERON:0001302	97.31	gold quality
apex of heart	UBERON:0002098	97.22	gold quality
ventricular zone	UBERON:0003053	97.20	gold quality
right lobe of liver	UBERON:0001114	96.95	gold quality
lower esophagus mucosa	UBERON:0035834	96.88	gold quality
right atrium auricular region	UBERON:0006631	96.82	gold quality
body of pancreas	UBERON:0001150	96.80	gold quality
left ovary	UBERON:0002119	96.79	gold quality
right hemisphere of cerebellum	UBERON:0014890	96.67	gold quality
esophagus mucosa	UBERON:0002469	96.57	gold quality
skin of abdomen	UBERON:0001416	96.52	gold quality
hindlimb stylopod muscle	UBERON:0004252	96.51	gold quality
ganglionic eminence	UBERON:0004023	96.49	gold quality
ectocervix	UBERON:0012249	96.48	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	96.47	gold quality
adenohypophysis	UBERON:0002196	96.43	gold quality
left uterine tube	UBERON:0001303	96.41	gold quality
gastrocnemius	UBERON:0001388	96.41	gold quality
skin of leg	UBERON:0001511	96.41	gold quality
right ovary	UBERON:0002118	96.36	gold quality
esophagus	UBERON:0001043	96.32	gold quality
cerebellar hemisphere	UBERON:0002245	96.30	gold quality
cerebellar cortex	UBERON:0002129	96.20	gold quality
tibial nerve	UBERON:0001323	96.18	gold quality
popliteal artery	UBERON:0002250	96.14	gold quality
lower esophagus	UBERON:0013473	96.14	gold quality
cardiac atrium	UBERON:0002081	96.13	gold quality
tibial artery	UBERON:0007610	96.13	gold quality
lower esophagus muscularis layer	UBERON:0035833	96.13	gold quality
heart left ventricle	UBERON:0002084	96.06	gold quality
muscle of leg	UBERON:0001383	95.96	gold quality
endocervix	UBERON:0000458	95.89	gold quality
mucosa of transverse colon	UBERON:0004991	95.89	gold quality
body of uterus	UBERON:0009853	95.89	gold quality
cardiac ventricle	UBERON:0002082	95.80	gold quality
left coronary artery	UBERON:0001626	95.79	gold quality
pituitary gland	UBERON:0000007	95.72	gold quality
stromal cell of endometrium	CL:0002255	95.71	gold quality
right adrenal gland cortex	UBERON:0035827	95.61	gold quality
right testis	UBERON:0004534	95.59	gold quality
aorta	UBERON:0000947	95.52	gold quality
heart	UBERON:0000948	95.48	gold quality
body of stomach	UBERON:0001161	95.47	gold quality
right adrenal gland	UBERON:0001233	95.47	gold quality
left testis	UBERON:0004533	95.46	gold quality
cortical plate	UBERON:0005343	95.37	gold quality
coronary artery	UBERON:0001621	95.34	gold quality
right lobe of thyroid gland	UBERON:0001119	95.33	gold quality
pancreas	UBERON:0001264	95.29	gold quality
left adrenal gland	UBERON:0001234	95.21	gold quality
left adrenal gland cortex	UBERON:0035825	95.18	gold quality
metanephros cortex	UBERON:0010533	95.15	gold quality
left lobe of thyroid gland	UBERON:0001120	95.04	gold quality
ascending aorta	UBERON:0001496	94.93	gold quality
omental fat pad	UBERON:0010414	94.86	gold quality
thoracic aorta	UBERON:0001515	94.84	gold quality
peritoneum	UBERON:0002358	94.84	gold quality
embryo	UBERON:0000922	94.83	gold quality
cerebellum	UBERON:0002037	94.81	gold quality
mucosa of stomach	UBERON:0001199	94.78	gold quality
minor salivary gland	UBERON:0001830	94.67	gold quality
adrenal cortex	UBERON:0001235	94.65	gold quality
thyroid gland	UBERON:0002046	94.65	gold quality
muscle organ	UBERON:0001630	94.64	gold quality
skeletal muscle organ	UBERON:0014892	94.64	gold quality
ovary	UBERON:0000992	94.58	gold quality
right frontal lobe	UBERON:0002810	94.54	gold quality
right coronary artery	UBERON:0001625	94.51	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	94.51	gold quality
adrenal gland	UBERON:0002369	94.50	gold quality
muscle layer of sigmoid colon	UBERON:0035805	94.50	gold quality
upper lobe of left lung	UBERON:0008952	94.45	gold quality
zone of skin	UBERON:0000014	94.41	gold quality
adipose tissue of abdominal region	UBERON:0007808	94.39	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	94.34	gold quality
testis	UBERON:0000473	94.31	gold quality
liver	UBERON:0002107	94.27	gold quality
stomach	UBERON:0000945	94.23	gold quality
amygdala	UBERON:0001876	94.22	gold quality
islet of Langerhans	UBERON:0000006	94.20	gold quality
mouth mucosa	UBERON:0003729	94.18	gold quality
nucleus accumbens	UBERON:0001882	94.17	gold quality
saliva-secreting gland	UBERON:0001044	94.12	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	94.00	gold quality
transverse colon	UBERON:0001157	93.92	gold quality
vagina	UBERON:0000996	93.84	gold quality
prostate gland	UBERON:0002367	93.78	gold quality
descending thoracic aorta	UBERON:0002345	93.54	gold quality
upper lobe of lung	UBERON:0008948	93.53	gold quality
prefrontal cortex	UBERON:0000451	93.51	gold quality
putamen	UBERON:0001874	93.48	gold quality
caudate nucleus	UBERON:0001873	93.39	gold quality
smooth muscle tissue	UBERON:0001135	93.33	gold quality
right lung	UBERON:0002167	93.19	gold quality
Brodmann (1909) area 9	UBERON:0013540	93.11	gold quality
spinal cord	UBERON:0002240	93.10	gold quality
spleen	UBERON:0002106	93.08	gold quality
rectum	UBERON:0001052	93.04	gold quality
cingulate cortex	UBERON:0003027	93.00	gold quality
small intestine Peyer’s patch	UBERON:0003454	92.92	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-GEOD-125970	yes	21.87
E-HCAD-10	yes	17.83
E-MTAB-8271	yes	6.56
E-ANND-3	no	0.00

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Skeletal muscle	tissue	80.6	not detected
Heart muscle	tissue	74.7	not detected
Tongue	tissue	69.0
Liver	tissue	62.7	not detected
Pancreas	tissue	61.0	low
Fallopian tube	tissue	60.4	high
Parathyroid gland	tissue	54.9	low
Vagina	tissue	52.8	high
Pituitary gland	tissue	50.8
Choroid plexus	tissue	47.7
Ovary	tissue	46.1	high
Esophagus	tissue	44.3	high
Salivary gland	tissue	40.1	not detected
Thymus	tissue	39.9
Adrenal gland	tissue	37.4	medium
Bone marrow	tissue	36.5	high
Skin 1	tissue	33.6	high
Hippocampus	tissue	33.5	not detected
Nucleus accumbens	tissue	33.3
Adipose tissue	tissue	31.5	not detected
Locus coeruleus	tissue	30.6
Colon	tissue	30.0	high
Lymph node	tissue	29.2	high
Stomach 1	tissue	28.2	high
Thyroid gland	tissue	28.2	medium
Cervix	tissue	28.1	high
Prostate	tissue	28.1	not detected
Breast	tissue	27.9	low
Tonsil	tissue	27.9	high
Appendix	tissue	27.2	high
Postcentral gyrus	tissue	26.8
Smooth muscle	tissue	25.7	low
Duodenum	tissue	25.6	high
Kidney	tissue	25.4	high
Urinary bladder	tissue	25.1	high
Seminal vesicle	tissue	24.8	low
Testis	tissue	24.3	high
Rectum	tissue	24.3	high
Placenta	tissue	23.0	high
Endometrium 1	tissue	22.6	medium
Small intestine	tissue	22.2	high
Lung	tissue	19.3	high
Spleen	tissue	19.1	low
Retina	tissue	15.5
Gallbladder	tissue	15.3	medium
Caudate putamen	tissue	14.8
Hippocampal formation	tissue	13.2
Frontal cortex	tissue	12.3
Spinal cord	tissue	12.0
Epididymis	tissue	11.5	low
Cerebral cortex	tissue	11.2	low
Somatosensory cortex	tissue	11.2
Basal ganglia	tissue	11.1	not detected
Cerebellum	tissue	10.6	low
Occipital cortex	tissue	10.1
Motor cortex	tissue	9.5
Prefrontal cortex	tissue	9.4
Putamen	tissue	9.4
Corpus callosum	tissue	9.4
Entorhinal cortex	tissue	9.3

Brain sub-regions (HPA Brain Atlas): detected in 191; highest nTPM — Posterior thalamic nucleus (59.5), Blood vessel (56.3), Medial dorsal thalamic nucleus (50.2), Medial geniculate body (47.9), Anterior thalamic nucleus, ventral (46.3).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CREB1, E2F4, JUN, MYC, NFIC, SP1, TFAP2A, TP53, TP63, TP73

miRNA regulators (miRDB)

Targeting POLD2 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

1 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3934-3P	99.76	65.51	1351

Functional genomics

gnomAD constraint: pLI 4.53e-08, LOEUF 0.93, missense Z 2.51 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000610533 splits into 3 regions with different missense tolerance; 1 is missense-constrained (≈6% of the expected missense variation). Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
7:44,114,788–44,115,822	98 / 138.6	0.71	no
7:44,115,823–44,116,124	8 / 34.1	0.23	yes (p 7.9e-06)
7:44,116,125–44,122,053	349 / 437.4	0.80	no
DepMap (CRISPR cell-line fitness): dependent in 97.7% of screened cell lines, common-essential.

Most-dependent cell lines (DepMap gene-effect, lower = stronger; ≤ −0.5 shown): MFE-280 (-2.071), HCC38 (-2.026), PA-TU-8988T (-2.006), KP-N-YN (-1.908), KP-N-SI9s (-1.808), LS1034 (-1.771), SK-N-FI (-1.724), S-117 (-1.717), 59M (-1.687), Caov-4 (-1.638), SNU-1033 (-1.603), SNU-5 (-1.562), HSC-4 (-1.555), PSN1 (-1.546), JM1 (-1.499).

Literature-anchored findings (GeneRIF, showing 14)

• the interaction of PCNA with DNA polymerase delta is mediated through the small subunit of the enzyme (PMID:11986310)
• The association of PDIP38 with pol delta was shown to occur in calf thymus tissue and mammalian cell extracts by GST-PDIP38 pull-down and coimmunoprecipitation experiments. (PMID:12522211)
• 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 p50 (PMID:18818516)
• Results suggest that POLD2 and KSP37 might be potential prognostic biomarkers. (PMID:21079801)
• DNA polymerase delta catalytic subunit p125 induced by mutant type p53 is associated with hepatocellular carcinoma invasion. (PMID:21372597)
• The results show that the FF483-484 amino acids in the human Poleta (designated F1 motif) are necessary for the interaction of this polymerase with POLD2, the B subunit of the replicative DNA polymerase delta, both in vitro and in vivo. (PMID:25662213)
• Inhibition of DNA polymerases a, delra and e by AFP promoter-driven artificial microRNAs may lead to effective growth arrest of AFP-positive HCC cells,as novel strategy for gene therapy (PMID:25924900)
• 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)
• 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)
• In patients from 2 independent pedigrees, we have identified what we believe to be a novel syndrome with reduced functionality of the polymerase delta complex caused by germline biallelic mutations in POLD1 or POLD2 as the underlying etiology of a previously unknown autosomal-recessive syndrome that combines replicative stress, neurodevelopmental abnormalities, and immunodeficiency. (PMID:31449058)
• ShRNA-based POLD2 expression knockdown sensitizes glioblastoma to DNA-Damaging therapeutics. (PMID:31954770)
• Polymerase delta promotes chromosomal rearrangements and imprecise double-strand break repair. (PMID:33077594)
• Exome sequencing reveals novel rare variants in Iranian familial multiple sclerosis: The importance of POLD2 in the disease pathogenesis. (PMID:34116171)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	pold2	ENSDARG00000095046
mus_musculus	Pold2	ENSMUSG00000020471
rattus_norvegicus	Pold2	ENSRNOG00000014098
drosophila_melanogaster	PolD2	FBGN0027903
caenorhabditis_elegans		WBGENE00008722

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1097163) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 7 distinct phenotype terms.

Mouse phenotype (MP)	Records
failure of blastocyst to hatch from the zona pellucida	2
embryonic lethality before implantation, complete penetrance	2
failure of embryo implantation	1
empty decidua capsularis	1
preweaning lethality, complete penetrance	1
abnormal sleep behavior	1
embryonic lethality prior to organogenesis	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	P49004	95.5%	Diamond
Arabidopsis thaliana	O48520	71.8%	Diamond
Oryza sativa Japonica Group	Q9LRE5	71.8%	Diamond
Xenopus laevis	O93610	70.9%	Diamond
Schizosaccharomyces pombe 972h-	P87324	34.7%	Diamond
Saccharomyces cerevisiae S288C	P46957	32.7%	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
MIR6838	ncRNA	102465504
AEBP1	protein-coding	165
POLM	protein-coding	27434
DBNL	protein-coding	28988
PGAM2	protein-coding	5224
MIR4649	ncRNA	100616346
GCK	protein-coding	2645
MYL7	protein-coding	58498
MIR6837	ncRNA	102466985

Protein

Protein identifiers

DNA polymerase delta subunit 2 — P49005 (reviewed: P49005)

Alternative names: DNA polymerase delta subunit p50

All UniProt accessions (16): A0A087WWF6, A0A8V8TMJ0, A0A8V8TMJ5, A0A8V8TMK0, A0A8V8TMZ6, A0A8V8TN02, A0A8V8TN07, A0A8V8TNY7, A0A8V8TPA1, A0A8V8TPA6, P49005, A0A8V8TPB6, C9IZD2, C9JHC7, C9JLE1, H7C1B3

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. 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. 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 DNA polymerase zeta complex. Along with POLD3, 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. 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 Pol-delta4, directly interacts with POLD1, POLD3 and POLD4. 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. Also observed as a dimeric complex with POLD2 (Pol-delta2 complex). Pol-delta2 is relatively insensitive to the PCNA stimulation (2-5-fold) compared to Pol-delta4 that is stimulated by over 50-fold. Contrary to the other components of Pol-delta4, does not directly interact with PCNA. As POLD1 and POLD4, 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. Directly interacts with POLDIP2 and POLDIP3. Directly interacts with KCTD13/PDIP1; in the presence of PCNA, this interaction may stimulate DNA polymerase activity. Component of the tetrameric Pol-zeta complex (Pol-zeta4), which consists of REV3L, MAD2L2, POLD2 and POLD3, with REV3L bearing DNA polymerase catalytic activity. Interacts with KCTD10.

Subcellular location. Nucleus.

Similarity. Belongs to the DNA polymerase delta/II small subunit family.

RefSeq proteins (3): NP_001120690, NP_001243808, NP_006221* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007185	DNA_pol_a/d/e_bsu	Domain
IPR024826	DNA_pol_delta/II_ssu	Family
IPR040663	DNA_pol_D_N	Domain
IPR041863	PolD2_C	Domain

Pfam: PF04042, PF18018

UniProt features (51 total): strand 22, helix 15, turn 4, modified residue 3, mutagenesis site 3, sequence variant 2, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

7 structures by resolution:

PDB	Title	Method	Resolution (Å)
3E0J	X-ray structure of the complex of regulatory subunits of human DNA polymerase delta	X-RAY DIFFRACTION	3
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-P49005-F1	89.42	0.75

Human Protein Atlas

Protein class: Metabolic proteins, Predicted intracellular proteins, Plasma proteins, Essential proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): nucleoplasm

Antibody reliability (HPA): IH approved · IF enhanced

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 (3)

Type	Positions
N-acetylmethionine	1
Phosphoserine	15, 257

Mutagenesis-validated functional residues (3)

Position	Phenotype
217	loss of pold3-binding in a yeast two-hybrid assay.
224	loss of pold3-binding in a yeast two-hybrid assay.
231	loss of pold3-binding in a yeast two-hybrid assay.

Function

Pathways and Gene Ontology

Reactome pathways

18 curated (TAS) of 43; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

43 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-9968295	Somatic hypermutation of immunoglobulin genes by error-prone mismatch repair (MMR)	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-9968297	Somatic hypermutation of immunoglobulin genes by error-prone base excision repair (BER)	electronic
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: 270 (showing top): REACTOME_DNA_REPLICATION, MODULE_52, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_DNA_STRAND_ELONGATION_INVOLVED_IN_DNA_REPLICATION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_DNA_DAMAGE_TOLERANCE, MODULE_16, KAUFFMANN_DNA_REPAIR_GENES, KEGG_HOMOLOGOUS_RECOMBINATION, MODULE_118, GOCC_NUCLEAR_REPLICATION_FORK, MUELLER_PLURINET, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_1, KEGG_MISMATCH_REPAIR

GO Biological Process (8): DNA replication (GO:0006260), DNA-templated DNA replication (GO:0006261), DNA strand elongation involved in DNA replication (GO:0006271), DNA repair (GO:0006281), error-prone translesion synthesis (GO:0042276), DNA biosynthetic process (GO:0071897), DNA metabolic process (GO:0006259), DNA damage response (GO:0006974)

GO Molecular Function (2): DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (4): nucleus (GO:0005634), nucleoplasm (GO:0005654), zeta DNA polymerase complex (GO:0016035), delta DNA polymerase complex (GO:0043625)

Reactome top-level categories

14 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
Somatic hypermutation of immunoglobulin genes	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

GO top-level categories

19 GO namespaces:

Category	Terms
DNA metabolic process	3
DNA replication	2
DNA polymerase complex	2
DNA biosynthetic process	1
DNA-templated DNA replication	1
DNA strand elongation	1
DNA synthesis involved in DNA replication	1
DNA damage response	1
translesion synthesis	1
nucleic acid biosynthetic process	1
nucleic acid metabolic process	1
cellular response to stress	1
nucleic acid binding	1
binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cellular anatomical structure	1
nuclear replisome	1
nuclear protein-containing complex	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 6 of 14 annotations. The rest are phylogenetic / computational / electronic (IEA).

6 experimentally-supported GO terms:

GO term	NS	Evidence
DNA biosynthetic process	BP	direct assay
DNA-templated DNA replication	BP	direct assay
error-prone translesion synthesis	BP	direct assay
delta DNA polymerase complex	CC	direct assay
nucleoplasm	CC	direct assay
zeta DNA polymerase complex	CC	direct assay

Protein interactions and networks

STRING

showing 15 of 1,381 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
POLD2	POLD3	Q15054	973
POLD2	POLD1	P28340	966
POLD2	PCNA	P12004	900
POLD2	POLD4	Q9HCU8	862
POLD2	POLDIP2	Q9Y2S7	779
POLD2	REV3L	O60673	772
POLD2	KCTD10	Q9H3F6	765
POLD2	MAD2L2	Q9UI95	737
POLD2	POLE2	P56282	718
POLD2	KCTD13	Q8WZ19	718
POLD2	REV1	Q9UBZ9	697
POLD2	POLA2	Q14181	690
POLD2	EXO1	Q9UQ84	690
POLD2	FEN1	P39748	682
POLD2	TNFAIP1	Q13829	670

IntAct

Human interaction partners of POLD2 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

15 partners by confidence:

Partner	Interaction type	MIscore	Records
POLD1	association	0.910	13
POLD3	direct interaction	0.890	5
POLD4	physical association	0.790	3
PCNA	physical association	0.680	2
REV3L	association	0.530	2
WRNIP1	physical association	0.500	1
CCHCR1	physical association	0.370	1
EP300	physical association	0.370	1
ERBB2	physical association	0.370	1
SOX12	physical association	0.370	1
TSG101	physical association	0.370	1
NUGGC	association	0.350	1
OFCC1	association	0.350	1
P4HA2	association	0.350	1
LSM6	physical association	0.000	1

BioGRID (117 interactions; top human partners by supporting records): POLD1 (Co-fractionation; 8 records), PCNA (Affinity Capture-Western; 7 records), POLD3 (Affinity Capture-MS; 5 records), MAD2L2 (Affinity Capture-Western; 4 records), POLD4 (Affinity Capture-MS; 4 records), AMZ1 (Affinity Capture-MS; 2 records), DKKL1 (Affinity Capture-MS; 2 records), ERP44 (Affinity Capture-MS; 2 records), MMS19 (Co-fractionation; 2 records), PARK2 (Affinity Capture-MS; 2 records), POLA2 (Co-fractionation; 2 records), POLH (Two-hybrid; 2 records), PPP5C (Affinity Capture-MS; 2 records), REV3L (Affinity Capture-MS; 2 records), SPRTN (Affinity Capture-MS; 2 records)

SIGNOR signaling

1 signaling interactions:

A	Effect	B	Mechanism
POLD2	“form complex”	“DNA polymerase delta”	binding

Protein complexes (CORUM) (9)

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

9 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 zeta	4	MAD2L2, POLD2, POLD3, REV3L
★ DNA polymerase delta	4	POLD1, POLD2, POLD3, POLD4
★ DNA polymerase delta, trimeric form	3	POLD1, POLD2, POLD3

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 15 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.

GO biological processes:

GO term	Partners	Fold	FDR
DNA synthesis involved in DNA repair	5	360.1×	2e-10
DNA-templated DNA replication	5	216.1×	1e-09

Disease & clinical

Genetic variants

Variant evidence for POLD2: 401 ClinVar records (0 pathogenic / likely pathogenic).

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	217
Likely benign	143
Benign	12

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 36 predictions of 1,052):

Position(s)	Effect	Δscore	Sites
7:44115764–44115765	donor_loss	1.0000	3
7:44116435	donor_gain	1.0000
7:44116511–44116512	acceptor_loss	1.0000	3
7:44116815–44116816	donor_loss	1.0000	4
7:44117016–44117017	acceptor_loss	1.0000	4
7:44118065–44118066	acceptor_loss	1.0000	2
7:44121832–44121833	donor_loss	1.0000	4
7:44114946–44114947	acceptor_loss	0.9900	4
7:44115293–44115294	donor_loss	0.9900	5
7:44115397–44115398	acceptor_loss	0.9900	6

AlphaMissense

1,111 missense substitutions predicted likely pathogenic (of 3,260 scored), across 299 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
D300	8	0.990	0.997
D220	8	0.987	0.997
D280	8	0.978	0.998
D391	8	0.972	0.990
F431	8	0.953	0.996
F452	8	0.946	0.994
D137	8	0.941	0.986
D293	8	0.941	0.980
D380	8	0.919	0.971
D131	8	0.913	0.974
F393	8	0.897	0.969
H312	8	0.892	0.989
F403	8	0.863	0.991
F171	8	0.849	0.988
F316	8	0.736	0.989
N330	7	0.979	0.998
F46	7	0.967	0.994
F39	7	0.960	0.978
F2	7	0.945	0.983
E136	7	0.937	0.975

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

6 prognostic cancer types:

Cancer	Prognostic	p-value
Liver Hepatocellular Carcinoma (TCGA)	unfavorable	8.75e-06
Liver Hepatocellular Carcinoma (validation)	unfavorable	1.15e-05
Lung Adenocarcinoma (TCGA)	unfavorable	2.14e-05
Kidney Chromophobe (TCGA)	unfavorable	5.59e-05
Head and Neck Squamous Cell Carcinoma (TCGA)	unfavorable	0.00019
Lung Adenocarcinoma (validation)	unfavorable	0.000708

Disease associations

OMIM: gene MIM:600815 | disease phenotypes:

GenCC curated gene-disease

1 curated gene-disease records:

Disease	Classification	Inheritance	Records
non-severe combined immunodeficiency due to polymerase delta deficiency	Moderate	Autosomal recessive

ClinGen Gene-Disease Validity

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

1 validity classifications:

Disease	Classification	Inheritance
non-severe combined immunodeficiency due to polymerase delta deficiency	Limited	AR

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (1 panels, 1 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

1 panels:

Panel	Rating
COVID-19 research	green

Mondo (1): non-severe combined immunodeficiency due to polymerase delta deficiency (MONDO:0800145)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2363042 (PROTEIN FAMILY), CHEMBL2763 (SINGLE PROTEIN)

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	2
cobaltous chloride	decreases expression	2
Hydrogen Peroxide	affects cotreatment, decreases reaction, increases expression	2
aristolochic acid I	decreases expression	1
TAK-243	increases sumoylation	1
bisphenol A	decreases expression	1
2,2’-methylenebis(4-methyl-6-tert-butylphenol)	affects expression, affects response to substance	1
sodium arsenate	decreases expression	1
benzo(e)pyrene	increases methylation	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
di-n-butylphosphoric acid	affects expression	1
K 7174	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
chromium histidinate	decreases reaction, increases expression	1
LDN 193189	affects cotreatment, increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Benzo(a)pyrene	increases methylation	1
Coumestrol	affects cotreatment, increases expression	1
Dichlorodiphenyl Dichloroethylene	increases expression	1
Estradiol	increases expression	1
Guanine	affects binding, decreases activity	1
Ivermectin	decreases expression	1
Mercury	affects expression	1
Methapyrilene	increases methylation	1
Oxygen	decreases expression	1
Quercetin	decreases expression	1
Quinic Acid	affects cotreatment, increases expression	1
Rotenone	decreases expression	1
Smoke	decreases expression	1
Thiram	decreases expression	1

ChEMBL screening assays

6 unique, capped per target: 6 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5697345	Binding	Inhibition of POLD2 (unknown origin) assessed as fold change at 10 uM incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. — *Nature*

Clinical trials (associated diseases)

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