POLN

Summary

POLN (DNA polymerase nu, HGNC:18870) is a protein-coding gene on chromosome 4p16.3, encoding DNA polymerase nu (Q7Z5Q5). DNA polymerase with very low fidelity that catalyzes considerable misincorporation by inserting dTTP opposite a G template, and dGTP opposite a T template.

This gene encodes a DNA polymerase type-A family member. The encoded protein plays a role in DNA repair and homologous recombination. This gene shares its 5’ exons with some transcripts from overlapping GeneID: 79441, which encodes an augmentin-like protein complex subunit.

Source: NCBI Gene 353497 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 158 total
• GTEx eGene: eQTL in 21 tissues, sQTL in 17 (q < 0.05)
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.02 (unconstrained)
• MANE Select transcript: NM_181808
• Notable: 158 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18870
Approved symbol	POLN
Name	DNA polymerase nu
Location	4p16.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000130997
Ensembl biotype	protein_coding
OMIM	610887
Entrez	353497

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 6 protein_coding, 6 protein_coding_CDS_not_defined, 4 retained_intron, 1 nonsense_mediated_decay

MANE Select: ENST00000511885

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

ENST00000511885, ENST00000382865, ENST00000503371, ENST00000503601, ENST00000506518, ENST00000508568, ENST00000509623, ENST00000510344, ENST00000511098, ENST00000511777, ENST00000514521, ENST00000514858, ENST00000515357, ENST00001026867, ENST00001118229, ENST00001122702, ENST00001141558

RefSeq mRNA: 1 — MANE Select: NM_181808 NM_181808

CCDS: CCDS3360

Canonical transcript exons

ENST00000511885 — 26 exons

Exon	Start	End
ENSE00000897203	2080958	2081036
ENSE00001288463	2071918	2072299
ENSE00003471895	2072968	2073029
ENSE00003473151	2131233	2131290
ENSE00003488950	2193204	2193316
ENSE00003494595	2229099	2229243
ENSE00003506470	2081633	2081743
ENSE00003513003	2242051	2242121
ENSE00003534336	2213047	2213126
ENSE00003540612	2207987	2208487
ENSE00003553786	2159155	2159211
ENSE00003567330	2129179	2129256
ENSE00003568696	2156788	2156853
ENSE00003578899	2174691	2174751
ENSE00003601529	2198524	2198717
ENSE00003603469	2075452	2075519
ENSE00003606593	2176266	2176334
ENSE00003612680	2085613	2085744
ENSE00003613523	2173955	2174019
ENSE00003618280	2128113	2128227
ENSE00003629677	2171098	2171181
ENSE00003630966	2170679	2170774
ENSE00003633935	2095851	2095933
ENSE00003663304	2179308	2179465
ENSE00003680492	2241520	2241790
ENSE00003689912	2157858	2157911

Expression profiles

Bgee: expression breadth ubiquitous, 160 present calls, max score 86.25.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 4.0187 / max 44.9892, expressed in 1482 samples.

Highest expression (Bgee): caudate nucleus, putamen, nucleus accumbens, frontal lobe, Brodmann (1909) area 9.

Genetic regulation across tissues (GTEx eQTL / sQTL)

POLN is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 21 tissues and its splicing (sQTL) in 17 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 38 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Testis	sqtl	4.6e-21	+1.14	4:2237380:GA:G
Cells Cultured fibroblasts	sqtl	1.6e-14	-0.87	4:2237380:GA:G
Testis	eqtl	1.1e-12	-0.49	4:2071570:T:C
Nerve Tibial	sqtl	2.1e-12	+0.72	4:2165641:C:T
Adipose Subcutaneous	sqtl	7.4e-08	-0.69	4:2212092:A:G
Brain Cerebellum	eqtl	1.4e-06	+0.83	4:2140137:G:C
Adrenal Gland	sqtl	1.2e-05	+1.00	4:2159167:C:T
Skin Sun Exposed Lower leg	sqtl	1.5e-05	-0.53	4:2185607:A:C
Brain Cerebellar Hemisphere	sqtl	2.2e-05	+0.98	4:2233148:G:A
Brain Cerebellar Hemisphere	eqtl	5.6e-05	+0.59	4:2173278:A:C
Breast Mammary Tissue	sqtl	1.2e-04	-0.59	4:2228611:C:T
Brain Cortex	sqtl	1.8e-04	-1.09	4:2139015:A:G
Brain Cerebellum	sqtl	8.6e-04	+0.93	4:2159167:C:T
Adrenal Gland	eqtl	1.6e-03	+0.40	4:2246106:T:C
Brain Frontal Cortex BA9	eqtl	2.6e-03	+0.37	4:2221343:G:C
Thyroid	eqtl	3.8e-03	-0.31	4:2139890:CAGAG:C
Skin Not Sun Exposed Suprapubic	eqtl	5.8e-03	+0.34	4:2233148:G:A
Nerve Tibial	eqtl	9.7e-03	-0.36	4:2231982:A:G
Skin Sun Exposed Lower leg	eqtl	1.1e-02	+0.27	4:2201649:T:C
Adipose Visceral Omentum	eqtl	1.1e-02	-0.66	4:2363657:G:A

FANTOM5 promoters

5 alternative TSS:

Promoter ID	TPM avg	Samples expressed
51109	4.0187	1482
51107	2.4718	874
51108	1.5590	922
51106	0.5361	216
51105	0.1876	48

Top tissues by expression

showing 100 of 236 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
caudate nucleus	UBERON:0001873	86.25	gold quality
putamen	UBERON:0001874	84.13	gold quality
nucleus accumbens	UBERON:0001882	82.13	gold quality
right frontal lobe	UBERON:0002810	82.10	gold quality
Brodmann (1909) area 9	UBERON:0013540	80.45	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.41	gold quality
anterior cingulate cortex	UBERON:0009835	79.80	gold quality
left testis	UBERON:0004533	79.60	gold quality
right testis	UBERON:0004534	79.39	gold quality
cerebellar hemisphere	UBERON:0002245	78.45	gold quality
cerebellar cortex	UBERON:0002129	78.35	gold quality
right hemisphere of cerebellum	UBERON:0014890	78.27	gold quality
omental fat pad	UBERON:0010414	77.74	gold quality
peritoneum	UBERON:0002358	77.72	gold quality
amygdala	UBERON:0001876	77.61	gold quality
right uterine tube	UBERON:0001302	77.55	gold quality
cerebellum	UBERON:0002037	77.52	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	77.15	gold quality
hypothalamus	UBERON:0001898	77.11	gold quality
testis	UBERON:0000473	77.01	gold quality
adipose tissue of abdominal region	UBERON:0007808	76.72	gold quality
vena cava	UBERON:0004087	75.23	gold quality
forebrain	UBERON:0001890	75.16	gold quality
brain	UBERON:0000955	75.01	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	74.79	gold quality
spinal cord	UBERON:0002240	74.33	gold quality
parotid gland	UBERON:0001831	73.65	gold quality
neocortex	UBERON:0001950	73.61	gold quality
substantia nigra	UBERON:0002038	73.42	gold quality
right adrenal gland cortex	UBERON:0035827	73.40	gold quality
lateral globus pallidus	UBERON:0002476	73.05	silver quality
midbrain	UBERON:0001891	73.01	gold quality
sural nerve	UBERON:0015488	73.00	gold quality
cerebral cortex	UBERON:0000956	72.95	gold quality
buccal mucosa cell	CL:0002336	72.93	gold quality
adenohypophysis	UBERON:0002196	72.76	gold quality
corpus callosum	UBERON:0002336	72.65	gold quality
right adrenal gland	UBERON:0001233	72.64	gold quality
frontal cortex	UBERON:0001870	72.62	gold quality
left coronary artery	UBERON:0001626	72.56	gold quality
coronary artery	UBERON:0001621	72.40	gold quality
Ammon’s horn	UBERON:0001954	72.12	gold quality
adrenal cortex	UBERON:0001235	72.01	gold quality
tibial nerve	UBERON:0001323	71.92	gold quality
left adrenal gland cortex	UBERON:0035825	71.84	gold quality
subcutaneous adipose tissue	UBERON:0002190	71.74	gold quality
left adrenal gland	UBERON:0001234	71.67	gold quality
adipose tissue	UBERON:0001013	71.56	gold quality
nipple	UBERON:0002030	71.42	gold quality
right coronary artery	UBERON:0001625	71.35	gold quality
pericardium	UBERON:0002407	71.32	silver quality
prefrontal cortex	UBERON:0000451	71.24	gold quality
mucosa of stomach	UBERON:0001199	71.22	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	71.18	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	70.94	gold quality
lower esophagus muscularis layer	UBERON:0035833	70.85	gold quality
subthalamic nucleus	UBERON:0001906	70.84	gold quality
lower esophagus	UBERON:0013473	70.83	gold quality
calcaneal tendon	UBERON:0003701	70.75	gold quality
body of tongue	UBERON:0011876	70.72	gold quality
pituitary gland	UBERON:0000007	70.64	gold quality
prostate gland	UBERON:0002367	70.51	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	70.51	gold quality
right ovary	UBERON:0002118	70.48	gold quality
cardia of stomach	UBERON:0001162	70.44	gold quality
endocervix	UBERON:0000458	70.43	gold quality
ventral tegmental area	UBERON:0002691	70.38	gold quality
cerebellar vermis	UBERON:0004720	70.37	gold quality
popliteal artery	UBERON:0002250	70.33	gold quality
tibial artery	UBERON:0007610	70.32	gold quality
tongue	UBERON:0001723	70.23	gold quality
trachea	UBERON:0003126	70.21	gold quality
lower esophagus mucosa	UBERON:0035834	70.21	gold quality
jejunum	UBERON:0002115	70.16	silver quality
adrenal gland	UBERON:0002369	70.14	gold quality
pharyngeal mucosa	UBERON:0000355	70.08	gold quality
thymus	UBERON:0002370	70.08	gold quality
superior surface of tongue	UBERON:0007371	70.08	gold quality
substantia nigra pars reticulata	UBERON:0001966	69.86	gold quality
aorta	UBERON:0000947	69.72	gold quality
pons	UBERON:0000988	69.67	silver quality
muscle layer of sigmoid colon	UBERON:0035805	69.64	gold quality
stromal cell of endometrium	CL:0002255	69.62	gold quality
temporal lobe	UBERON:0001871	69.62	gold quality
synovial joint	UBERON:0002217	69.46	silver quality
left ovary	UBERON:0002119	69.43	gold quality
cardiac atrium	UBERON:0002081	69.33	gold quality
right atrium auricular region	UBERON:0006631	69.32	gold quality
bone marrow cell	CL:0002092	69.31	gold quality
gall bladder	UBERON:0002110	69.22	gold quality
metanephros cortex	UBERON:0010533	69.17	gold quality
ascending aorta	UBERON:0001496	69.13	gold quality
descending thoracic aorta	UBERON:0002345	69.13	gold quality
jejunal mucosa	UBERON:0000399	69.12	silver quality
fundus of stomach	UBERON:0001160	68.97	gold quality
layer of synovial tissue	UBERON:0007616	68.96	gold quality
muscle of leg	UBERON:0001383	68.91	gold quality
thoracic aorta	UBERON:0001515	68.89	gold quality
trigeminal ganglion	UBERON:0001675	68.89	gold quality
gastrocnemius	UBERON:0001388	68.83	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	4.88

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 65 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM
Cerebellum	tissue	13.2
Olfactory bulb	tissue	12.4
Substantia nigra	tissue	9.4
Spinal cord	tissue	9.4
Hippocampal formation	tissue	9.3
Midbrain	tissue	9.2
Pons	tissue	9.1
Putamen	tissue	9.1
Amygdala	tissue	9.1
Medulla oblongata	tissue	9.1
Cerebral cortex	tissue	8.9
Motor cortex	tissue	8.9
Thalamus	tissue	8.8
Hypothalamus	tissue	8.8
Corpus callosum	tissue	8.8
Periaqueductal gray	tissue	8.8
Superior colliculi	tissue	8.7
Septum	tissue	8.7
Prefrontal cortex	tissue	8.5
Entorhinal cortex	tissue	8.5
Occipital cortex	tissue	8.5
Retrosplenial and cingulate cortex	tissue	8.4
Retrosplenial cortex	tissue	8.3
Somatosensory cortex	tissue	8.2
Temporal cortex	tissue	8.1
Basal ganglia	tissue	8.0
Insular cortex	tissue	8.0
Ventral forebrain	tissue	7.9
Adipose tissue	tissue	2.2
Nucleus accumbens	tissue	2.2
Hippocampus	tissue	2.0
Postcentral gyrus	tissue	2.0
Testis	tissue	1.4
Locus coeruleus	tissue	1.3
Epididymis	tissue	0.7
Choroid plexus	tissue	0.6
Breast	tissue	0.4
Salivary gland	tissue	0.4
Liver	tissue	0.3
Gallbladder	tissue	0.3
Kidney	tissue	0.3
Prostate	tissue	0.3
Pituitary gland	tissue	0.2
Retina	tissue	0.2
Seminal vesicle	tissue	0.2
Adrenal gland	tissue	0.2
Fallopian tube	tissue	0.2
Cervix	tissue	0.1
Skin 1	tissue	0.1
Lymph node	tissue	0.1
Stomach 1	tissue	0.1
Heart muscle	tissue	0.1
Ovary	tissue	0.1
Vagina	tissue	0.1
Parathyroid gland	tissue	0.1
Smooth muscle	tissue	0.1
Colon	tissue	0.1
Urinary bladder	tissue	0.1
Tongue	tissue	0.1
Frontal cortex	tissue	0.1

Brain sub-regions (HPA Brain Atlas): detected in 189; highest nTPM — Ventral spinal cord (9.4), Dorsal hippocampus (9.3), Dorsal spinal cord (9.2), White matter (8.8), Subiculum (8.7).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

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

5 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6749-3P	99.00	65.73	1443
HSA-MIR-4717-5P	98.19	67.97	894
HSA-MIR-5699-5P	97.36	67.03	1014
HSA-MIR-1288-3P	96.86	66.95	536
HSA-MIR-3189-3P	96.80	66.34	896

Functional genomics

gnomAD constraint: pLI 1.52e-20, LOEUF 1.02, missense Z 0.411 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000511885 — one region, missense o/e 1.02.

Literature-anchored findings (GeneRIF, showing 25)

• identification as homolog to Mus308 (PMID:12794064)
• pol nu error rates for all 12 single base-base mismatches and for insertion and deletion errors (PMID:17118716)
• The DNA cross-linking agent mitomycin C hypersensitivity of PolN knockdown cells is rescued by overexpression of DNA polymerase-proficient PolN but not by DNA polymerase-deficient PolN. (PMID:19908865)
• The recently discovered polymerase POLN identified here is involved in repair of DNA cross-links. (PMID:19995904)
• Described is a novel translesion DNA synthesis substrate specificity of pol nu, demonstrating that it is able to bypass exceptionally large DNA lesions whose linkages are through the DNA major groove. (PMID:20102227)
• Our finding suggests that polymorphisms in DNA repair genes, POLN and PRKDC, were associated with increased melanoma risk in melanoma families with and without CDKN2A mutations. (PMID:21671477)
• The lower fidelity of POLN compared to that of Klenow fragment of Escherichia coli can be attributed to a much lower catalytic efficiency for correct dNTP incorporation, whereas both enzymes have similar kinetic parameters for G-dTTP misinsertion. (PMID:22008035)
• both yeast and human pol eta synthesize past the 3’-(m)C CPD in a >99% error-free manner, consistent with the highly water-exposed nature of the active site. (PMID:22262850)
• Epstein-Barr virus BPLF1 deubiquitinates PCNA and attenuates polymerase eta recruitment to DNA damage sites (PMID:22623772)
• WRN improves the efficiency and fidelity of hpol eta to promote more effective replication of DNA. (PMID:23045531)
• Pol nu catalyzes both correct and mispair formation with high catalytic efficiency. (PMID:25963146)
• This is the first crystal structure of a DNA polymerase with an incoming rNTP opposite a DNA lesion. (PMID:26740629)
• The Proliferating Cell Nuclear Antigen (PCNA)-interacting Protein (PIP) Motif of DNA Polymerase eta Mediates Its Interaction with the C-terminal Domain of Rev1. (PMID:26903512)
• Five x-ray crystal structures of hpol eta ternary complexes were determined, three at the insertion and two at the extension stage. (PMID:27226627)
• The structural data are consistent with the observed tendency of hpol eta to insert both dC and dT opposite the O(6)-MeG lesion with similar efficiencies. (PMID:27694439)
• Data suggest that translesion DNA synthesis mediated by (1) POLI-dependent pathway (2) REV1- and POLN-dependent pathway, or (3) POLtheta-dependent pathway occur in predominantly error-free manner in human cells. (POLI = DNA polymerase iota; REV1 = DNA repair protein-REV1; POLN = DNA polymerase nu; POLtheta = DNA polymerase theta) (PMID:29330301)
• Crystallographic evidence for two-metal-ion catalysis in human pol eta. (PMID:30368948)
• the Poleta-oxaliplatin-GpG structure provides a structural basis for TLS-mediated bypass of the major oxaliplatin-DNA adducts and insights into resistance to platinum-based chemotherapy in humans. (PMID:30709915)
• These results suggest that hpol eta is one of the major reverse transcriptases involved in physiological processes in human cells. (PMID:30842261)
• The roles of polymerases nu and theta in replicative bypass of O (6)- and N (2)-alkyl-2’-deoxyguanosine lesions in human cells. (PMID:32098870)
• Translesion synthesis of the major nitrogen mustard-induced DNA lesion by human DNA polymerase eta. (PMID:33175093)
• Multiple deprotonation paths of the nucleophile 3’-OH in the DNA synthesis reaction. (PMID:34088846)
• DNA polymerases eta and kappa bypass N(2)-guanine-O(6)-alkylguanine DNA alkyltransferase cross-linked DNA-peptides. (PMID:34461101)
• Next-Generation Sequencing-Based Analysis of the Roles of DNA Polymerases nu and theta in the Replicative Bypass of 8-Oxo-7,8-dihydroguanine in Human Cells. (PMID:35815634)
• Rare POLN mutations confer risk for familial nasopharyngeal carcinoma through weakened Epstein-Barr virus lytic replication. (PMID:36116213)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	poln	ENSDARG00000103961
mus_musculus	Poln	ENSMUSG00000045102
rattus_norvegicus	Haus3	ENSRNOG00000069005

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:2675617) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 1 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal meiosis	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
Mycobacterium tuberculosis variant bovis AF2122/97	P0A551	100.0%	Diamond
Mycobacterium tuberculosis CDC1551	P9WNU4	100.0%	Diamond
Mycobacterium tuberculosis H37Rv	P9WNU5	100.0%	Diamond
Thermus thermophilus HB8	P52028	99.0%	Diamond
Streptococcus pneumoniae TIGR4	P59199	99.0%	Diamond
Streptococcus pneumoniae R6	P59200	99.0%	Diamond
Thermus caldophilus	P80194	99.0%	Diamond
Lactococcus cremoris subsp. cremoris MG1363	O32801	94.2%	Diamond
Lactococcus lactis subsp. lactis Il1403	Q9CDS1	94.2%	Diamond
Rickettsia felis Marseille-URRWFXCal2	Q9RAA9	94.0%	Diamond
Rickettsia helvetica	Q9RLB6	94.0%	Diamond
Escherichia coli K-12	P00582	93.9%	Diamond
Helicobacter pylori 26695	P56105	93.9%	Diamond
Salmonella enterica subsp. enterica serovar Typhimurium str. LT2	Q9F173	93.9%	Diamond
Helicobacter pylori J99	Q9ZJE9	93.9%	Diamond
Rickettsia prowazekii str. Madrid E	O05949	90.6%	Diamond
Rickettsia typhi str. Wilmington	Q9RLA0	90.6%	Diamond
Rickettsia conorii str. Malish 7	Q92GB7	89.0%	Diamond
Thermus aquaticus	P19821	87.5%	Diamond
Geobacillus stearothermophilus	P52026	87.1%	Diamond
[Bacillus] caldotenax	Q04957	87.1%	Diamond
Thermus thermophilus	P30313	85.8%	Diamond
Mycobacterium leprae TN	P46835	85.2%	Diamond
Rickettsia bellii RML369-C	Q1RH76	83.3%	Diamond
Thermus filiformis	O52225	79.3%	Diamond
Bacillus subtilis subsp. subtilis str. 168	O34996	68.1%	Diamond
Haemophilus influenzae Rd KW20	P43741	62.8%	Diamond
Pseudomonas aeruginosa PAO1	Q9HT80	62.1%	Diamond
Deinococcus radiodurans R1 = ATCC 13939 = DSM 20539	P52027	47.6%	Diamond
Drosophila melanogaster	O18475	44.6%	Diamond
Rhizobium leguminosarum	Q9S1G2	44.4%	Diamond
Caldicellulosiruptor bescii DSM 6725	Q59156	43.8%	Diamond
Chloroflexus aurantiacus J-10-fl	O08307	42.9%	Diamond
Borreliella burgdorferi B31	O51498	41.6%	Diamond
Treponema pallidum subsp. pallidum str. Nichols	P74933	39.7%	Diamond
Synechocystis sp. PCC 6803 substr. Kazusa	Q55971	38.6%	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
MIR4800	ncRNA	100616358
MXD4	protein-coding	10608
ASPNAT	protein-coding	339983
ZFYVE28	protein-coding	57732
HAUS3	protein-coding	79441
NICOL1	protein-coding	401115
MIR943	ncRNA	100126332
SCARNA22	ncRNA	677770
NSD2	protein-coding	7468
NELFA	protein-coding	7469
RNF4-DT	ncRNA	107986250
CFAP99	protein-coding	402160

Protein

Protein identifiers

DNA polymerase nu — Q7Z5Q5 (reviewed: Q7Z5Q5)

All UniProt accessions (2): H0YA88, Q7Z5Q5

UniProt curated annotations — full annotation on UniProt →

Function. DNA polymerase with very low fidelity that catalyzes considerable misincorporation by inserting dTTP opposite a G template, and dGTP opposite a T template. Is the least accurate of the DNA polymerase A family (i.e. POLG, POLN and POLQ). Can perform accurate translesion DNA synthesis (TLS) past a 5S-thymine glycol. Can perform efficient strand displacement past a nick or a gap and gives rise to an amount of product similar to that on non-damaged template. Has no exonuclease activity. Error-prone DNA polymerase that preferentially misincorporates dT regardless of template sequence. May play a role in TLS during interstrand cross-link (ICL) repair. May be involved in TLS when genomic replication is blocked by extremely large major groove DNA lesions. May function in the bypass of some DNA-protein and DNA-DNA cross-links. May have a role in cellular tolerance to DNA cross-linking agents. Involved in the repair of DNA cross-links and double-strand break (DSB) resistance. Participates in FANCD2-mediated repair. Forms a complex with HELQ helicase that participates in homologous recombination (HR) repair and is essential for cellular protection against DNA cross-links.

Subunit / interactions. Interacts with FANCD2, FANCI, PCNA, RAD51 and HELQ.

Subcellular location. Nucleus.

Tissue specificity. Highly expressed in testis and heart. Weakly expressed in skeletal muscle.

Activity regulation. Inhibited by ddTTP.

Similarity. Belongs to the DNA polymerase type-A family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q7Z5Q5-1	1	yes
Q7Z5Q5-3	2

RefSeq proteins (1): NP_861524* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001098	DNA-dir_DNA_pol_A_palm_dom	Domain
IPR002298	DNA_polymerase_A	Family
IPR036397	RNaseH_sf	Homologous_superfamily
IPR040940	DNA_pol_P_Exo	Domain
IPR043502	DNA/RNA_pol_sf	Homologous_superfamily

Pfam: PF00476, PF18049

Catalyzed reactions (Rhea)

• DNA(n) + a 2’-deoxyribonucleoside 5’-triphosphate = DNA(n+1) + diphosphate (RHEA:22508)

UniProt features (78 total): helix 32, strand 23, sequence variant 8, turn 4, mutagenesis site 3, region of interest 2, compositionally biased region 2, splice variant 2, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

4 structures by resolution:

PDB	Title	Method	Resolution (Å)
4XVK	Binary complex of human polymerase nu and DNA with the finger domain closed	X-RAY DIFFRACTION	2.95
4XVI	Binary complex of human polymerase nu and DNA with the finger domain ajar	X-RAY DIFFRACTION	3.1
4XVM	Binary complex of human polymerase nu and DNA with the finger domain closed and thumb …	X-RAY DIFFRACTION	3.2
4XVL	Binary complex of human polymerase nu and DNA with the finger domain open	X-RAY DIFFRACTION	3.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q7Z5Q5-F1	75.70	0.56

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Transferases, Metabolic proteins, Predicted intracellular proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): nucleoplasm

Antibody reliability (HPA): 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.

Mutagenesis-validated functional residues (3)

Position	Phenotype
623	abolishes catalytic activity.
675	reduces polymerase activity. no effect on accuracy.
679	no effect on polymerase activity. increases accuracy by ten-fold.

Function

Pathways and Gene Ontology

Reactome pathways

1 curated (TAS) of 2; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

2 pathways:

ID	Pathway	Evidence
R-HSA-6783310	Fanconi Anemia Pathway	curated
R-HSA-73894	DNA Repair	—

MSigDB gene sets: 59 (showing top): GOBP_DNA_DAMAGE_TOLERANCE, KAUFFMANN_DNA_REPAIR_GENES, GOMF_DNA_POLYMERASE_ACTIVITY, GOBP_DNA_DAMAGE_RESPONSE, chr4p16, GOBP_DNA_BIOSYNTHETIC_PROCESS, GOBP_INTERSTRAND_CROSS_LINK_REPAIR, REACTOME_FANCONI_ANEMIA_PATHWAY, REACTOME_DNA_REPAIR, GOBP_RECOMBINATIONAL_REPAIR, BURTON_ADIPOGENESIS_12, GOBP_DNA_REPLICATION, BURTON_ADIPOGENESIS_6, MARSON_BOUND_BY_FOXP3_UNSTIMULATED, MARSON_BOUND_BY_E2F4_UNSTIMULATED

GO Biological Process (9): double-strand break repair via homologous recombination (GO:0000724), DNA-templated DNA replication (GO:0006261), double-strand break repair (GO:0006302), translesion synthesis (GO:0019985), interstrand cross-link repair (GO:0036297), DNA replication (GO:0006260), DNA repair (GO:0006281), DNA damage response (GO:0006974), DNA biosynthetic process (GO:0071897)

GO Molecular Function (8): DNA binding (GO:0003677), DNA-directed DNA polymerase activity (GO:0003887), cyclin binding (GO:0030332), nucleic acid binding (GO:0003676), protein binding (GO:0005515), transferase activity (GO:0016740), nucleotidyltransferase activity (GO:0016779), DNA polymerase activity (GO:0034061)

GO Cellular Component (2): nucleus (GO:0005634), nucleoplasm (GO:0005654)

Reactome top-level categories

1 top-level categories:

Category	Pathways
DNA Repair	1

GO top-level categories

22 GO namespaces:

Category	Terms
DNA metabolic process	3
DNA repair	2
DNA biosynthetic process	2
binding	2
recombinational repair	1
double-strand break repair	1
DNA replication	1
DNA damage tolerance	1
DNA synthesis involved in DNA replication	1
DNA damage response	1
cellular response to stress	1
nucleic acid biosynthetic process	1
nucleic acid binding	1
DNA polymerase activity	1
protein binding	1
catalytic activity	1
transferase activity, transferring phosphorus-containing groups	1
nucleotidyltransferase activity	1
catalytic activity, acting on DNA	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cellular anatomical structure	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 7 of 19 annotations. The rest are phylogenetic / computational / electronic (IEA).

7 experimentally-supported GO terms:

GO term	NS	Evidence
double-strand break repair via homologous recombination	BP	mutant phenotype
interstrand cross-link repair	BP	mutant phenotype
translesion synthesis	BP	direct assay
nucleoplasm	CC	direct assay
nucleus	CC	direct assay
DNA-directed DNA polymerase activity	MF	direct assay
cyclin binding	MF	physical interaction

Protein interactions and networks

STRING

showing 15 of 891 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
POLN	HELQ	Q8TDG4	974
POLN	POLA1	P09884	929
POLN	REV3L	O60673	598
POLN	POLM	Q9NP87	595
POLN	PRIMPOL	Q96LW4	570
POLN	REV1	Q9UBZ9	561
POLN	POLL	Q9UGP5	541
POLN	POLK	Q9UBT6	520
POLN	FANCD2	Q9BXW9	476
POLN	MAD2L2	Q9UI95	463
POLN	TMEM132D	Q14C87	437
POLN	HAUS3	Q68CZ6	435
POLN	POLQ	O75417	434
POLN	RPA3	P35244	433
POLN	FANCM	Q8IYD8	432

IntAct

BioGRID (47 interactions; top human partners by supporting records): PCNA (Affinity Capture-Western; 5 records), BRCA1 (Affinity Capture-MS; 3 records), BRIP1 (Affinity Capture-MS; 2 records), FANCD2 (Co-localization; 2 records), HELQ (Affinity Capture-Western; 2 records), POLDIP2 (Reconstituted Complex; 2 records), RAD18 (Affinity Capture-Western; 2 records), ACTR10 (Negative Genetic), ARL2 (Negative Genetic), ATR (Biochemical Activity), BARD1 (Affinity Capture-MS), BRCA2 (Affinity Capture-MS), CASP10 (Cross-Linking-MS (XL-MS)), CDC23 (Negative Genetic), CDC27 (Negative Genetic)

Disease & clinical

Genetic variants

Variant evidence for POLN: 158 ClinVar records (0 pathogenic / likely pathogenic); 4 GWAS associations.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	114
Likely benign	15
Benign	3

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 31 predictions of 3,700):

Position(s)	Effect	Δscore	Sites
4:2170779	acceptor_gain	1.0000
4:2171096–2171097	donor_loss	1.0000	5
4:2171182	acceptor_gain	1.0000
4:2171182–2171183	acceptor_loss	1.0000	4
4:2171188	acceptor_gain	1.0000
4:2174035	acceptor_gain	1.0000
4:2198718–2198719	acceptor_loss	1.0000	6
4:2213045–2213046	donor_loss	1.0000	5
4:2213127–2213128	acceptor_loss	1.0000	4
4:2213128–2213130	acceptor_gain	1.0000	3

AlphaMissense

856 missense substitutions predicted likely pathogenic (of 5,907 scored), across 279 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
D803	8	0.916	0.985
D348	8	0.913	0.958
F654	8	0.911	0.988
H802	8	0.904	0.954
D774	8	0.859	0.926
D623	8	0.849	0.931
W562	7	0.943	0.992
W852	7	0.926	0.987
W661	7	0.923	0.986
F624	7	0.916	0.968
F476	7	0.903	0.981
E428	7	0.897	0.946
F711	7	0.878	0.969
E628	7	0.862	0.936
F424	7	0.852	0.925
F489	7	0.845	0.962
W354	7	0.841	0.940
R608	7	0.839	0.967
N765	7	0.837	0.959
F721	7	0.827	0.957

HPA cancer prognostics

RNA cancer specificity: Cancer enhanced (Prostate Adenocarcinoma)

Disease associations

OMIM: gene MIM:610887 | disease phenotypes:

GWAS associations

4 associations:

Study	Trait	p-value
GCST006630_82	Diastolic blood pressure	6e-13
GCST008839_365	Height	7e-9
GCST001342_6	Alzheimer’s disease	6e-6
GCST007637_34	Diffusing capacity of carbon monoxide	8e-6

EFO canonical traits (from GWAS)

2 canonical traits:

EFO ID	Trait name
EFO:0006336	diastolic blood pressure
EFO:0009369	diffusing capacity of the lung for carbon monoxide

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2010628 (SINGLE PROTEIN)

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

19 total (human), top 19 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation	2
aristolochic acid I	increases expression	1
N6-(2-hydroxy-3-buten-1-yl)-2’-deoxyadenosine	decreases activity	1
bisphenol A	affects cotreatment, decreases methylation	1
diepoxybutane	affects binding, decreases activity, decreases reaction	1
ferrous chloride	decreases expression	1
2’-deoxyadenosine	decreases reaction, affects binding, decreases activity	1
CGP 52608	affects binding, increases reaction	1
abrine	decreases expression	1
(+)-JQ1 compound	increases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Arsenic	affects methylation	1
Silicon Dioxide	decreases expression	1
Smoke	increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Aflatoxin B1	decreases methylation	1
Antirheumatic Agents	decreases expression	1
Acrylamide	increases expression	1
Particulate Matter	increases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2013672	Binding	Inhibition of C-terminal-His6-tagged human pol nu expressed in Escherichia coli assessed as inhibition of incorporation of dTTP into poly(dA)/oligo(dT)18 after 60 mins	Pinophilins A and B, inhibitors of mammalian A-, B-, and Y-family DNA polymerases and human cancer cell proliferation. — *J Nat Prod*

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_F5CR	EDITGENE POLN Knockout HAP1 Cell Line	Cancer cell line	Male
CVCL_TF09	HAP1 POLN (-) 1	Cancer cell line	Male
CVCL_TF10	HAP1 POLN (-) 2	Cancer cell line	Male
CVCL_TF11	HAP1 POLN (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

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

showing 60 of 300 trials:

NCT	Phase	Status	Title
NCT00029224	Phase 4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00035997	Phase 4	COMPLETED	Open-label Trial on the Effect of I.V. Zoledronic Acid 4 mg on Bone Density in Hormone Sensitive Prostate Cancer Patients With Bone Metastasis
NCT00063609	Phase 4	COMPLETED	The Effect of Zoledronic Acid on Bone Loss in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy
NCT00103623	Phase 4	SUSPENDED	The Plenaxis® Experience Study
NCT00106392	Phase 4	COMPLETED	A Safety and Efficacy Study of Prograf in the Prevention of Erectile Dysfunction After Radical Prostatectomy
NCT00185029	Phase 4	UNKNOWN	MR-Lymphography and Lymph Node Staging in Prostate Cancer
NCT00199485	Phase 4	COMPLETED	Angelica Sinensis for the Treatment of Hot Flashes in Men Undergoing LHRH Therapy for Prostate Cancer
NCT00219219	Phase 4	COMPLETED	Zoledronic Acid in the Prevention of Skeletal-related Events in Hormone Refractory and Hormone-sensitive Prostate Cancer Patients With Bone Metastases
NCT00219271	Phase 4	COMPLETED	Effect Of Zoledronic Acid On Circulating And Bone Marrow-Residing Prostate Cancer Cells In Patients With Clinically Localized Prostate Cancer
NCT00237146	Phase 4	COMPLETED	Study to Evaluate Zoledronic Acid on Quality of Life and Skeletal-related Events as Adjuvant Treatment in Patients With Hormone-naïve Prostate Cancer and Bone Metastasis Who Have Undergone Orchiectomy
NCT00242554	Phase 4	COMPLETED	Open-label Phase IV Clinical Trial to Evaluate the Safety and Tolerability of Zoledronic Acid in Patients With Prostate Cancer and Bone Metastases
NCT00280098	Phase 4	COMPLETED	Docetaxel in the Treatment of Hormone Refractory Prostate Cancer
NCT00293696	Phase 4	COMPLETED	Casodex/Zoladex Biomarkers in Localised Prostate Cancer
NCT00334139	Phase 4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00375765	Phase 4	COMPLETED	Effects On Dihydrotestosterone Regulated Gene Expression In Benign Prostatic Hyperplasia Or Prostate Cancer
NCT00391690	Phase 4	COMPLETED	Evaluation of Bone Markers as Diagnostic Tools for Early Detection of Bone Metastases in Patients With High Risk Prostate Cancer
NCT00422708	Phase 4	COMPLETED	Local Anesthesia for Prostate Biopsy
NCT00526331	Phase 4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00590213	Phase 4	COMPLETED	Compare the Value of Prophylactic Versus Therapeutic Breast Radiotherapy in CASODEX
NCT00629330	Phase 4	TERMINATED	Dissemination of Prostate Cancer Screening to PCP’s in African American Communities
NCT00771966	Phase 4	COMPLETED	Radical Prostatectomy and Perioperative Fluid Therapy
NCT00805701	Phase 4	COMPLETED	Study Assessing The Efficacy And Safety Of Avodart (Dutasteride) At Improving Urinary Symptoms In Men With Prostate Cancer Who Are Undergoing Seed Implantation
NCT00859027	Phase 4	COMPLETED	Effect Of Risedronate On Bone Mass In Older Men Receiving Neoadjuvant Therapy For Prostate Cancer
NCT00906269	Phase 4	UNKNOWN	Can Hyperbaric Oxygen Improve Erectile Function Following Surgery for Prostate Cancer
NCT00953277	Phase 4	COMPLETED	Study of Nerve Reconstruction Using AVANCE in Subjects Who Undergo Robotic Assisted Prostatectomy for Treatment of Prostate Cancer
NCT00982800	Phase 4	COMPLETED	Does Postoperative Gabapentin Reduce Pain, Opioid Consumption and Anxiety and Have a Positive Effect on Health Related Quality of Life After Radical Prostatectomy?
NCT01083199	Phase 4	COMPLETED	Global Performance Evaluation of the AMS CONTINUUM™ Device
NCT01136226	Phase 4	COMPLETED	Evaluate Recovery of Testosterone for Patients Using Eligard
NCT01161563	Phase 4	COMPLETED	Randomized Crossover Trial to Assess the Tolerability of Gonadotropin Releasing Hormone (GnRH) Analogue Administration
NCT01230905	Phase 4	COMPLETED	Study to Monitor the Effects of Androgen Suppression Treatment on the Heart
NCT01296672	Phase 4	COMPLETED	3 Month Finasteride Challenge Test Can Significantly Improve the Performance of Screening for Prostate Cancer
NCT01365143	Phase 4	TERMINATED	Prospective Randomized Trial Comparing Robotic Versus Open Radical Prostatectomy
NCT01379742	Phase 4	UNKNOWN	Comparison of Between ThinSeed™ and OncoSeed™ for Permanent Prostate Brachytherapy
NCT01486563	Phase 4	COMPLETED	Hydroxyethyl Starch and Renal Function After Radical Prostatectomy
NCT01511874	Phase 4	COMPLETED	Efficacy and Safety Study of ELIGARD 22.5mg With Prostate Cancer
NCT01512472	Phase 4	TERMINATED	Firmagon (Degarelix) Intermittent Therapy
NCT01547416	Phase 4	COMPLETED	The Effect of Combined General/Epidural Anesthesia Versus General Anesthesia on Diaphragmatic Function
NCT01571544	Phase 4	COMPLETED	The Use of Thermal Suits as Preventing Hypothermia During Surgery
NCT01581749	Phase 4	UNKNOWN	Evaluation of Truebeam for Low-Intermediate Risk Prostate Cancer
NCT01649635	Phase 4	COMPLETED	Study of Cabazitaxel Combined With Prednisone and Prophylaxis of Neutropenia Complications in the Treatment of Patients With Metastatic Castration-resistant Prostate Cancer
NCT01673984	Phase 4	TERMINATED	GP Extended Action Triptorelin
NCT01753297	Phase 4	COMPLETED	A Study of Immediate 9 Months Adjuvant Hormone Therapy With Triptorelin 11.25 mg Versus Active Surveillance After Radical Prostatectomy in High Risk Prostate Cancer Patients.
NCT01794793	Phase 4	COMPLETED	Study to Allow Access to Pasireotide for Patients Benefiting From Pasireotide Treatment in Novartis-sponsored Studies
NCT01950871	Phase 4	TERMINATED	Prostate Guided Biopsy Study Evaluating the Diagnostic Performance of Prostate HistoScanning
NCT01995513	Phase 4	COMPLETED	Safety Study of Continued Enzalutamide Treatment In Prostate Cancer Patients
NCT02102646	Phase 4	COMPLETED	MRI Substudy; Metabolic Changes Due to Iatrogenic Hypogonadism
NCT02116582	Phase 4	COMPLETED	A Study to Evaluate Enzalutamide After Abiraterone in Metastatic Castration-Resistant Prostate Cancer
NCT02149628	Phase 4	COMPLETED	The Effect of Propofol Based Total Intravenous Anesthesia on Oxidative Stress and Nitric Oxide
NCT02405858	Phase 4	COMPLETED	A Study of Abiraterone Acetate in Metastatic Castration-Resistant Prostate Cancer Participants Who Responded Poorly to the First-line Combined Androgen Blockade Therapy
NCT02441517	Phase 4	TERMINATED	A Study of Enzalutamide Re-treatment in Metastatic Castration-resistant Prostate Cancer After Docetaxel and/or Cabazitaxel Treatment
NCT02441894	Phase 4	COMPLETED	Combination of Cabazitaxel With Prednisolone With Primary Prophylaxis With PEG-G-CSF in Treatment of Patients With Prostate Cancer
NCT02475057	Phase 4	COMPLETED	Endothelial Function in Prostate Cancer Patients on Degarelix vs. Luteinizing Hormone-Releasing Hormone Agonists
NCT02511665	Phase 4	UNKNOWN	Metformin And Longevity
NCT02651948	Phase 4	COMPLETED	Transperineal, MRI-guided, Prostate Biopsy
NCT02721433	Phase 4	COMPLETED	4-weekly Versus 12-weekly Administration of Bone-targeted Agents in Patients With Bone Metastases
NCT02726009	Phase 4	COMPLETED	A Trial to Evaluate Safety of Firmagon® (Degarelix) in Indian Patients Diagnosed With Advanced Hormone-dependent Prostate Cancer
NCT02749825	Phase 4	TERMINATED	Comparison of Trelstar Versus Lupron or Zoladex in Advanced Prostate Cancer
NCT02757365	Phase 4	UNKNOWN	Efficiency Study of Aspirin to Prevent the Occurrence of Prostate Cancer
NCT02773251	Phase 4	COMPLETED	The Effect of Guardix-solution for the Prevention of Postoperative Intestinal Adhesion and Intestinal Obstruction After Laparoscopic Pelvic Cavity Surgery
NCT02812186	Phase 4	COMPLETED	Deep Versus Moderate Neuromuscular Blockade During Laparoscopic Surgery

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for POLN across ~30M SureChEMBL compounds — explore on Sugi Predict.