POLA1

Summary

POLA1 (DNA polymerase alpha 1, catalytic subunit, HGNC:9173) is a protein-coding gene on chromosome Xp22.11-p21.3, encoding DNA polymerase alpha catalytic subunit (P09884). Catalytic subunit of the DNA polymerase alpha complex (also known as the alpha DNA polymerase-primase complex) which plays an essential role in the initiation of DNA synthesis. It is a selective cancer dependency (DepMap: 85.9% of cell lines).

This gene encodes the catalytic subunit of DNA polymerase, which together with a regulatory and two primase subunits, forms the DNA polymerase alpha complex. The catalytic subunit plays an essential role in the initiation of DNA replication.

Source: NCBI Gene 5422 — RefSeq curated summary.

At a glance

• Gene–disease (curated): X-linked intellectual disability, van Esch type (Definitive, GenCC) — +1 more curated relationship
• GWAS associations: 2
• Clinical variants (ClinVar): 1,104 total — 6 pathogenic, 6 likely-pathogenic
• Phenotypes (HPO): 83
• Druggable target: yes — 3 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 85.9% of screened cell lines
• MANE Select transcript: NM_001330360

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9173
Approved symbol	POLA1
Name	DNA polymerase alpha 1, catalytic subunit
Location	Xp22.11-p21.3
Locus type	gene with protein product
Status	Approved
Aliases	p180
Ensembl gene	ENSG00000101868
Ensembl biotype	protein_coding
OMIM	312040
Entrez	5422

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 10 protein_coding, 5 protein_coding_CDS_not_defined, 5 retained_intron, 1 nonsense_mediated_decay

ENST00000379059, ENST00000379068, ENST00000480125, ENST00000493342, ENST00000494204, ENST00000611764, ENST00000672178, ENST00000676703, ENST00000677083, ENST00000677890, ENST00000677939, ENST00000678249, ENST00000678847, ENST00000679301, ENST00000854652, ENST00000933041, ENST00000933042, ENST00000933043, ENST00000933044, ENST00000972056, ENST00000972057

RefSeq mRNA: 3 — MANE Select: NM_001330360 NM_001330360, NM_001378303, NM_016937

CCDS: CCDS14214, CCDS83462

Canonical transcript exons

ENST00000379068 — 37 exons

Exon	Start	End
ENSE00000667346	24723155	24723267
ENSE00000863236	24699425	24699549
ENSE00000863237	24703251	24703347
ENSE00000863238	24704389	24704469
ENSE00000863239	24714554	24714669
ENSE00000863240	24715141	24715203
ENSE00000863241	24716362	24716454
ENSE00000863242	24716884	24716971
ENSE00000863243	24717290	24717491
ENSE00000863244	24717580	24717758
ENSE00000863245	24725981	24726055
ENSE00000978374	24841652	24841830
ENSE00000978375	24843546	24843677
ENSE00001108234	24742002	24742121
ENSE00001108236	24737625	24737741
ENSE00001108240	24733755	24733816
ENSE00001108250	24739375	24739550
ENSE00001108255	24735399	24735488
ENSE00001108259	24745418	24745542
ENSE00001108261	24743230	24743329
ENSE00001108263	24741375	24741504
ENSE00001175630	24888006	24888122
ENSE00001175661	24812658	24812863
ENSE00001247042	24930453	24930549
ENSE00001247222	24724335	24724451
ENSE00001330832	24810708	24810800
ENSE00001479660	24995805	24996986
ENSE00001479766	24693918	24694004
ENSE00003471824	24727782	24727936
ENSE00003504528	24748311	24748460
ENSE00003564447	24821452	24821583
ENSE00003581288	24826427	24826601
ENSE00003594201	24748870	24748992
ENSE00003616251	24814979	24815111
ENSE00003637264	24809898	24809930
ENSE00003678306	24732370	24732454
ENSE00003693499	24726933	24727071

Expression profiles

Bgee: expression breadth ubiquitous, 231 present calls, max score 90.09.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.5165 / max 250.4997, expressed in 1630 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
195801	11.5165	1630

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	90.09	gold quality
sural nerve	UBERON:0015488	89.79	gold quality
calcaneal tendon	UBERON:0003701	89.16	gold quality
oocyte	CL:0000023	87.81	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	86.89	gold quality
ganglionic eminence	UBERON:0004023	86.28	gold quality
tendon	UBERON:0000043	85.61	gold quality
colonic epithelium	UBERON:0000397	84.81	gold quality
secondary oocyte	CL:0000655	84.59	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.20	gold quality
embryo	UBERON:0000922	83.26	gold quality
bone marrow cell	CL:0002092	81.63	gold quality
adrenal tissue	UBERON:0018303	80.56	gold quality
corpus callosum	UBERON:0002336	80.43	gold quality
gastrocnemius	UBERON:0001388	79.30	gold quality
muscle of leg	UBERON:0001383	79.26	gold quality
tonsil	UBERON:0002372	79.01	gold quality
tibial nerve	UBERON:0001323	78.80	gold quality
bone marrow	UBERON:0002371	78.65	gold quality
popliteal artery	UBERON:0002250	78.16	gold quality
tibial artery	UBERON:0007610	78.15	gold quality
ovary	UBERON:0000992	77.79	gold quality
ectocervix	UBERON:0012249	77.76	gold quality
left ovary	UBERON:0002119	77.72	gold quality
rectum	UBERON:0001052	77.58	gold quality
hindlimb stylopod muscle	UBERON:0004252	77.50	gold quality
mucosa of transverse colon	UBERON:0004991	77.40	gold quality
hair follicle	UBERON:0002073	77.30	gold quality
skin of abdomen	UBERON:0001416	77.24	gold quality
cervix squamous epithelium	UBERON:0006922	77.21	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-6678	yes	7.71
E-ANND-3	yes	6.55
E-MTAB-7606	no	21.74

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CUX1, E2F1, GABPA, MYC, SP1

miRNA regulators (miRDB)

46 targeting POLA1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-204-5P	99.79	71.62	2439
HSA-MIR-211-5P	99.79	71.65	2440
HSA-MIR-4517	99.76	69.19	1867
HSA-MIR-4499	99.62	67.29	1470
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-7159-5P	99.53	72.12	2472
HSA-MIR-7159-3P	99.51	70.17	1920
HSA-MIR-4643	99.49	67.63	1791
HSA-MIR-4688	99.48	64.68	828
HSA-MIR-6743-5P	99.48	63.60	721
HSA-MIR-569	99.42	66.32	1009
HSA-MIR-377-3P	99.37	70.18	1905
HSA-MIR-5582-5P	99.27	71.42	1879
HSA-MIR-5690	99.25	67.58	1012
HSA-MIR-6760-5P	98.87	66.73	1515
HSA-MIR-629-5P	98.78	68.72	1032
HSA-MIR-3611	98.76	68.76	1290
HSA-MIR-4272	98.76	68.74	1810

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 85.9% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 28)

• Human cell DNA replication is mediated by a discrete multiprotein complex. The peak of DNA polymerase alpha activity co-purifies with the peak of in vitro SV40 DNA replication activity. (PMID:11968016)
• correlation between binding of CDP/Cux to the DNA pol alpha promoter and the stimulation of gene expression (PMID:12665598)
• Data show that human DNA polymerase alpha and the Klenow fragment of Escherichia coli DNA polymerase I (KF) incorporate all four nucleotide analogues opposite all four canonical bases up to 4000-fold more efficiently than incorrect natural bases. (PMID:12950174)
• Three-dimensional structures of the zinc finger motif in the carboxy terminus of the human DNA polymerase-alpha were determined in this study. (PMID:14499601)
• YB-1 mediates DNA polymerase alpha gene expression (PMID:15615704)
• nonphosphorylated p68 inhibited the stimulation of pol-alpha activity by hyperphosphorylated retinoblastoma protein, suggesting that p68 might impede the association of ppRb with p180 (PMID:16935576)
• During dNTP polymerization, it uses a combination of negative (N-1 and N-3) and positive (N-1 and N-6) selectivity to differentiate between right and wrong dNTPs, while the shape of the base pair is essentially irrelevant. (PMID:17209555)
• These results argue that cells can tolerate low levels of p180 as long as Mcm10 is present to “recycle” it. (PMID:17699597)
• And-1/Ctf4 is therefore a new replication initiation factor that brings together the MCM2-7 helicase and the DNA pol alpha-primase complex. (PMID:17761813)
• Results show that depletion of DNA polymerase alpha and not Polepsilon or Poldelta by siRNA induces phosphorylation of Chk1 on Ser345, thus phenocopying antimetabolite exposure. (PMID:19177015)
• DNA and p180 binding to an Mcm10 construct that contains both the ID and CTD, provide the first mechanistic insight into how Mcm10 might use a handoff mechanism to load and stabilize pol alpha within the replication fork. (PMID:19608746)
• Findings indicate that tethering of primase to the replisome by DNA polymerase alpha (pol alpha) is critical for the normal action of DNA replication forks in eukaryotic cells. (PMID:22593576)
• Depletion of p180 in U2OS cells increases cell size. (PMID:22679391)
• Pol epsilon and Pol alpha/delta seem to pursue their functions at least in part independently in late S phase (PMID:22887995)
• The Pol alpha-primase complex. (PMID:22918585)
• the N-terminal domain of the large subunit of primase (p58N) directly interacts with the C-terminal domain of the catalytic subunit of polalpha (p180C) (PMID:24962573)
• To understand the regulatory mechanisms and to reveal the details of DNA polymerase alpha organization, the study determined the crystal structure of p70 in complex with C terminus of the POLA catalytic subunit (p180C). (PMID:25847248)
• 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)
• Data indicate that X-linked reticulate pigmentary disorder (XLPDR) is caused by an intronic mutation that disrupts the expression of POLA1, which encodes the catalytic subunit of DNA polymerase-alpha. (PMID:27019227)
• Mutation in POLA1 is responsible for XLPDR (MIM: 312040) and demonstrates a role for this gene in interferon regulation (PMID:27019227)
• The first crystal structure of human Polalpha polymerase subunit in complex with a DNA:DNA helix shows that portion of the DNA:DNA helix in contact with the polymerase is not in a B-form but in a hybrid A-B form. The free energy cost of distorting DNA from B- to hybrid A-B form may augur the termination of primer synthesis. (PMID:27032819)
• Divalent ions attenuate DNA synthesis by human DNA polymerase alpha by changing the structure of the template/primer or by perturbing the polymerase reaction. (PMID:27235627)
• High POLA1 expression is associated with bladder cancer. (PMID:28320388)
• We propose that completely skewed XCI favoring the normal X chromosome resulted from death of cells with an active derivative X that was caused by a non-functional POLA1 gene. In summary, we conclude that functional monosomy of 6q27-qter and functional disomy of Xpter-p22.11 are responsible for the clinical phenotype of the patient (PMID:28371302)
• detailed structural comparison of Polalpha with other replicative DNA polymerases disclosed common features and some differences, which may reflect the specialization of each polymerase in genome replication (PMID:29555682)
• Defective DNA Polymerase alpha-Primase Leads to X-Linked Intellectual Disability Associated with Severe Growth Retardation, Microcephaly, and Hypogonadism. (PMID:31006512)
• Pol alpha-primase dependent nuclear localization of the mammalian CST complex. (PMID:33731801)
• Small tandem DNA duplications result from CST-guided Pol alpha-primase action at DNA break termini. (PMID:34376693)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	pola1	ENSDARG00000045308
mus_musculus	Pola1	ENSMUSG00000006678
rattus_norvegicus	Pola1	ENSRNOG00000013322
drosophila_melanogaster	PolA1	FBGN0259113
caenorhabditis_elegans		WBGENE00012936

Paralogs (3): REV3L (ENSG00000009413), NEXMIF (ENSG00000050030), POLD1 (ENSG00000062822)

Protein

Protein identifiers

DNA polymerase alpha catalytic subunit — P09884 (reviewed: P09884)

Alternative names: DNA polymerase alpha catalytic subunit p180

All UniProt accessions (4): P09884, A0A5F9ZHW2, A0A7I2V2V3, A6NMQ1

UniProt curated annotations — full annotation on UniProt →

Function. Catalytic subunit of the DNA polymerase alpha complex (also known as the alpha DNA polymerase-primase complex) which plays an essential role in the initiation of DNA synthesis. During the S phase of the cell cycle, the DNA polymerase alpha complex (composed of a catalytic subunit POLA1, a regulatory subunit POLA2 and two primase subunits PRIM1 and PRIM2) is recruited to DNA at the replicative forks via direct interactions with MCM10 and WDHD1. The primase subunit of the polymerase alpha complex initiates DNA synthesis by oligomerising short RNA primers on both leading and lagging strands. These primers are initially extended by the polymerase alpha catalytic subunit and subsequently transferred to polymerase delta and polymerase epsilon for processive synthesis on the lagging and leading strand, respectively. The reason this transfer occurs is because the polymerase alpha has limited processivity and lacks intrinsic 3’ exonuclease activity for proofreading error, and therefore is not well suited for replicating long complexes. In the cytosol, responsible for a substantial proportion of the physiological concentration of cytosolic RNA:DNA hybrids, which are necessary to prevent spontaneous activation of type I interferon responses.

Subunit / interactions. Component of the alpha DNA polymerase complex (also known as the alpha DNA polymerase-primase complex) consisting of four subunits: the catalytic subunit POLA1, the regulatory subunit POLA2, and the primase complex subunits PRIM1 and PRIM2 respectively. Interacts with PARP1; this interaction functions as part of the control of replication fork progression. Interacts with MCM10 and WDHD1; these interactions recruit the polymerase alpha complex to the pre-replicative complex bound to DNA. Interacts with RPA1; this interaction stabilizes the replicative complex and reduces the misincorporation rate of DNA polymerase alpha by acting as a fidelity clamp. (Microbial infection) Interacts with SV40 Large T antigen; this interaction allows viral DNA replication. (Microbial infection) Interacts with herpes simplex virus 1/HHV-1 replication origin-binding protein UL9.

Subcellular location. Nucleus. Cytoplasm. Cytosol.

Post-translational modifications. A 165 kDa form is probably produced by proteolytic cleavage at Lys-124.

Disease relevance. Pigmentary disorder, reticulate, with systemic manifestations, X-linked (PDR) [MIM:301220] An X-linked recessive disorder characterized by recurrent infections and sterile inflammation in various organs. Diffuse skin hyperpigmentation with a distinctive reticulate pattern is universally evident by early childhood. This is later followed in many patients by hypohidrosis, corneal inflammation and scarring, enterocolitis that resembles inflammatory bowel disease, and recurrent urethral strictures. Melanin and amyloid deposition is present in the dermis. Affected males also have a characteristic facies with frontally upswept hair and flared eyebrows. Female carriers have only restricted pigmentary changes along Blaschko’s lines. The disease is caused by variants affecting the gene represented in this entry. XLPDR is caused by a recurrent intronic mutation that results in missplicing and reduced POLA1 expression. This leads to a decrease in cytosolic RNA:DNA hybrids and constitutive activation of type I interferon responses, but has no effect on cell replication. Van Esch-O’Driscoll syndrome (VEODS) [MIM:301030] An X-linked recessive syndrome characterized by different degrees of intellectual disability, moderate to severe short stature, microcephaly, hypogonadism, and variable congenital malformations. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Autoinhibited in apo-primosome, where the zinc motif of POLA1 and oligonucleotide/olicosaccharide-binding domain of POLA2 are placed into the active site blocking RNA:DNA duplex entry.

Domain organisation. The CysA-type zinc finger is required for PCNA-binding.

Miscellaneous. In eukaryotes there are five DNA polymerases: alpha, beta, gamma, delta, and epsilon which are responsible for different reactions of DNA synthesis.

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

RefSeq proteins (3): NP_001317289, NP_001365232, NP_058633 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006133	DNA-dir_DNA_pol_B_exonuc	Domain
IPR006134	DNA-dir_DNA_pol_B_multi_dom	Domain
IPR006172	DNA-dir_DNA_pol_B	Family
IPR012337	RNaseH-like_sf	Homologous_superfamily
IPR015088	Znf_DNA-dir_DNA_pol_B_alpha	Domain
IPR017964	DNA-dir_DNA_pol_B_CS	Conserved_site
IPR023211	DNA_pol_palm_dom_sf	Homologous_superfamily
IPR024647	DNA_pol_a_cat_su_N	Domain
IPR036397	RNaseH_sf	Homologous_superfamily
IPR038256	Pol_alpha_znc_sf	Homologous_superfamily
IPR042087	DNA_pol_B_thumb	Homologous_superfamily
IPR043502	DNA/RNA_pol_sf	Homologous_superfamily
IPR045846	POLBc_alpha	Domain

Pfam: PF00136, PF03104, PF08996, PF12254

Enzyme classification (BRENDA):

• EC 2.7.7.102 — DNA primase AEP (BRENDA: 9 organisms, 25 substrates, 3 inhibitors, 8 Km, 5 kcat entries)

Substrate kinetics (BRENDA)

5 substrates with measured Km, best-characterized 5. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
DNTP	5–198	3
5’-CTTCTTCTGTGC-3'	0.2	1
ATP	0.15	1
DATP	0.032	1
NTP	27.5	1

Catalyzed reactions (Rhea), 1 shown:

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

UniProt features (147 total): strand 56, helix 47, turn 10, binding site 8, modified residue 7, region of interest 5, sequence variant 4, sequence conflict 4, compositionally biased region 2, chain 1, zinc finger region 1, site 1, short sequence motif 1

Structure

Experimental structures (PDB)

21 structures.

PDB	Method	Resolution (Å)
4QCL	X-RAY DIFFRACTION	2.2
4Y97	X-RAY DIFFRACTION	2.51
4Q5V	X-RAY DIFFRACTION	2.52
7N2M	X-RAY DIFFRACTION	2.9
6AS7	X-RAY DIFFRACTION	2.95
8VY3	ELECTRON MICROSCOPY	2.98
8QJ7	ELECTRON MICROSCOPY	3.07
5IUD	X-RAY DIFFRACTION	3.3
8D96	ELECTRON MICROSCOPY	3.35
9C8V	ELECTRON MICROSCOPY	3.39
8B9D	ELECTRON MICROSCOPY	3.4
8D0B	ELECTRON MICROSCOPY	3.43
9MJ5	ELECTRON MICROSCOPY	3.5
8D9D	ELECTRON MICROSCOPY	3.59
5EXR	X-RAY DIFFRACTION	3.6
7OPL	ELECTRON MICROSCOPY	4.12
8D0K	ELECTRON MICROSCOPY	4.27
7U5C	ELECTRON MICROSCOPY	4.6
1K0P	SOLUTION NMR
1K18	SOLUTION NMR
1N5G	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P09884-F1	76.36	0.47

Functional residue map

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

Catalytic / active sites (1): 124–125 (cleavage)

Ligand- & substrate-binding residues (8): 1283; 1286; 1310; 1315; 1348; 1353; 1371; 1374

Post-translational modifications (7): 174, 186, 190, 209, 224, 406, 970

Function

Pathways and Gene Ontology

Reactome pathways

10 pathways

ID	Pathway
R-HSA-113501	Inhibition of replication initiation of damaged DNA by RB1/E2F1
R-HSA-174411	Polymerase switching on the C-strand of the telomere
R-HSA-174430	Telomere C-strand synthesis initiation
R-HSA-68952	DNA replication initiation
R-HSA-68962	Activation of the pre-replicative complex
R-HSA-69091	Polymerase switching
R-HSA-69166	Removal of the Flap Intermediate
R-HSA-69183	Processive synthesis on the lagging strand
R-HSA-69205	G1/S-Specific Transcription
R-HSA-9710421	Defective pyroptosis

MSigDB gene sets: 553 (showing top): E2F_Q4, REACTOME_INHIBITION_OF_REPLICATION_INITIATION_OF_DAMAGED_DNA_BY_RB1_E2F1, REACTOME_DNA_REPLICATION, E2F_Q4_01, HORIUCHI_WTAP_TARGETS_DN, REACTOME_G1_S_SPECIFIC_TRANSCRIPTION, TGCGCANK_UNKNOWN, E2F4DP1_01, MORF_MSH3, GOBP_CELLULAR_RESPONSE_TO_UV, GOBP_CELL_CYCLE_DNA_REPLICATION, GOBP_CELLULAR_RESPONSE_TO_LIGHT_STIMULUS, MORF_BRCA1, MORF_ATRX, GOBP_DNA_STRAND_ELONGATION_INVOLVED_IN_DNA_REPLICATION

GO Biological Process (12): DNA synthesis involved in DNA repair (GO:0000731), DNA replication (GO:0006260), DNA replication, synthesis of primer (GO:0006269), DNA replication initiation (GO:0006270), DNA strand elongation involved in DNA replication (GO:0006271), leading strand elongation (GO:0006272), lagging strand elongation (GO:0006273), DNA repair (GO:0006281), double-strand break repair via nonhomologous end joining (GO:0006303), regulation of type I interferon production (GO:0032479), mitotic DNA replication initiation (GO:1902975), DNA-templated DNA replication (GO:0006261)

GO Molecular Function (14): nucleotide binding (GO:0000166), DNA binding (GO:0003677), chromatin binding (GO:0003682), DNA replication origin binding (GO:0003688), single-stranded DNA binding (GO:0003697), DNA-directed DNA polymerase activity (GO:0003887), zinc ion binding (GO:0008270), protein kinase binding (GO:0019901), nucleic acid binding (GO:0003676), protein binding (GO:0005515), transferase activity (GO:0016740), nucleotidyltransferase activity (GO:0016779), DNA polymerase activity (GO:0034061), metal ion binding (GO:0046872)

GO Cellular Component (9): chromatin (GO:0000785), nucleus (GO:0005634), nuclear envelope (GO:0005635), nucleoplasm (GO:0005654), alpha DNA polymerase:primase complex (GO:0005658), nucleolus (GO:0005730), cytosol (GO:0005829), nuclear matrix (GO:0016363), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-9 pathways:

Category	Pathways
Telomere C-strand (Lagging Strand) Synthesis	2
G1/S Transition	2
Lagging Strand Synthesis	2
E2F mediated regulation of DNA replication	1
Synthesis of DNA	1
DNA Replication Pre-Initiation	1
Leading Strand Synthesis	1
Processive synthesis on the lagging strand	1
Diseases of programmed cell death	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
DNA biosynthetic process	3
DNA metabolic process	3
DNA-templated DNA replication	3
binding	3
nuclear lumen	3
DNA replication	2
DNA replication, synthesis of primer	2
DNA strand elongation involved in DNA replication	2
DNA replication, removal of RNA primer	2
DNA repair	1
RNA biosynthetic process	1
DNA strand elongation	1
DNA synthesis involved in DNA replication	1
DNA damage response	1
double-strand break repair	1
regulation of cytokine production	1
type I interferon production	1
nuclear cell cycle DNA replication initiation	1
mitotic DNA replication	1
mitotic cell cycle process	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
nucleic acid binding	1
sequence-specific double-stranded DNA binding	1
DNA binding	1
DNA polymerase activity	1
transition metal ion binding	1
kinase binding	1
catalytic activity	1
transferase activity, transferring phosphorus-containing groups	1
nucleotidyltransferase activity	1
catalytic activity, acting on DNA	1
cation binding	1
chromosome	1
intracellular membrane-bounded organelle	1
nucleus	1
endomembrane system	1
organelle envelope	1
DNA polymerase complex	1

Protein interactions and networks

STRING

2924 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
POLA1	POLA2	Q14181	995
POLA1	PRIM2	P49643	991
POLA1	PRIM1	P49642	987
POLA1	POLN	Q7Z5Q5	933
POLA1	HELQ	Q8TDG4	917
POLA1	POLE2	P56282	848
POLA1	POLD2	P49005	744
POLA1	MCM6	Q14566	715
POLA1	POLE3	Q9NRF9	688
POLA1	CDC6	Q99741	684
POLA1	POLD1	P28340	682
POLA1	CTC1	Q2NKJ3	681
POLA1	MCM3	P25205	675
POLA1	ARX	Q96QS3	668
POLA1	SUPT16H	Q9Y5B9	639

IntAct

73 interactions, top by confidence:

A	B	Type	Score
CDK8	MED19	psi-mi:“MI:2364”(proximity)	0.850
	POLA1	psi-mi:“MI:0915”(physical association)	0.770
POLA1		psi-mi:“MI:0915”(physical association)	0.770
	POLA1	psi-mi:“MI:2364”(proximity)	0.770
	POLA1	psi-mi:“MI:0407”(direct interaction)	0.770
MAD2L1	INSR	psi-mi:“MI:0914”(association)	0.700
rep	POLA1	psi-mi:“MI:0914”(association)	0.670
PRIM1	POLA1	psi-mi:“MI:0914”(association)	0.640
POLA1	PRIM1	psi-mi:“MI:0914”(association)	0.640
	POLA1	psi-mi:“MI:0915”(physical association)	0.560
POLA1		psi-mi:“MI:0915”(physical association)	0.560
POLA1		psi-mi:“MI:2364”(proximity)	0.560
rep	POLA1	psi-mi:“MI:0914”(association)	0.530
STN1	SMCO3	psi-mi:“MI:0914”(association)	0.530
POLR3H	POLR3A	psi-mi:“MI:0914”(association)	0.530
MAD2L1	PPIP5K2	psi-mi:“MI:0914”(association)	0.530
DDX21	MED19	psi-mi:“MI:2364”(proximity)	0.480
POLA1	E1	psi-mi:“MI:2364”(proximity)	0.450
E1	POLA1	psi-mi:“MI:0915”(physical association)	0.450
H3C1	SMCHD1	psi-mi:“MI:2364”(proximity)	0.410
SMC1A	POLA1	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (192): POLA1 (Affinity Capture-RNA), POLA1 (Affinity Capture-RNA), POLA1 (Affinity Capture-RNA), POLA1 (Affinity Capture-RNA), POLA1 (Affinity Capture-MS), POLA1 (Affinity Capture-MS), POLA1 (Affinity Capture-MS), POLA1 (Affinity Capture-MS), POLA1 (Affinity Capture-MS), POLA1 (Affinity Capture-MS), POLA1 (Affinity Capture-MS), LIG1 (Co-fractionation), POLA1 (Co-fractionation), POLA1 (Co-fractionation), POLA1 (Co-fractionation)

ESM2 similar proteins: A0A1P8ASY1, A1YVX4, A2VDX7, A3KMI0, A3LNL5, C5DIF1, C5DXZ1, F1Q514, O13836, O89042, P09543, P09884, P13233, P16330, P29375, P41229, P41230, Q29FC1, Q2KHZ2, Q30DN6, Q38JA7, Q3UXZ9, Q58DC8, Q5F3R2, Q5RFD0, Q5XI06, Q5XUN4, Q62240, Q69ZS7, Q6CVT0, Q6FJK6, Q6IQX0, Q6PGC1, Q75A64, Q7Z478, Q80Y84, Q8BJL0, Q8LI34, Q99MK2, Q9BY66

Diamond homologs: A7U6F1, A7U6F2, A7U6F3, P09884, P15436, P18131, P41712, P74918, Q779J8, Q94636, Q9FHA3, A4KX57, O00874, O48653, O89042, O93745, P0C971, P13382, P26019, P27727, P28040, P30317, P33609, P77933, Q27152, Q54SV8, Q58295, Q9DE46, O26310, O33845, O59610, P0C972, P0C973, P0C974, P42489, P43139, Q07635, Q5UQR0, O27276, O48901

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
PARP1	“up-regulates activity”	POLA1	binding
POLA1	up-regulates	DNA_replication
MCM10	“up-regulates quantity by stabilization”	POLA1	relocalization
RPA1	“up-regulates activity”	POLA1	binding
POLA1	“form complex”	“DNA polymerase alpha:primase complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 70 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
mRNA Splicing	5	11.4×	4e-03
CHD1 and CHD2 subfamily	5	11.3×	4e-03
Processing of Capped Intron-Containing Pre-mRNA	6	10.3×	2e-03
mRNA Polyadenylation	5	9.2×	8e-03
mRNA Splicing - Major Pathway	7	8.0×	2e-03
Dengue Virus-Host Interactions	7	6.7×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

1104 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	6
Uncertain significance	459
Likely benign	317
Benign	71

Top pathogenic / likely-pathogenic (12)

Variant ID	HGVS	Classification
224980	NM_001330360.2(POLA1):c.1393-354A>G	Pathogenic
627632	NM_001330360.2(POLA1):c.254T>G (p.Ile85Ser)	Pathogenic
627633	NM_001330360.2(POLA1):c.4160C>T (p.Pro1387Leu)	Pathogenic
627634	NM_001330360.2(POLA1):c.525+1G>A	Pathogenic
627635	NM_016937.3(POLA1):c.445_507del	Pathogenic
627636	NM_001330360.2(POLA1):c.346G>A (p.Gly116Arg)	Pathogenic
2626807	NM_001330360.2(POLA1):c.1864A>G (p.Arg622Gly)	Likely pathogenic
2626813	NM_001330360.2(POLA1):c.3455A>G (p.Tyr1152Cys)	Likely pathogenic
2626814	NM_001330360.2(POLA1):c.1627C>A (p.Leu543Ile)	Likely pathogenic
4082195	NM_001330360.2(POLA1):c.2121T>G (p.Ile707Met)	Likely pathogenic
807658	NM_001330360.2(POLA1):c.1207G>A (p.Asp403Asn)	Likely pathogenic
816323	GRCh37/hg19 Xp22.11-21.3(chrX:24860361-25221642)x3	Likely pathogenic

SpliceAI

8000 predictions. Top by Δscore:

Variant	Effect	Δscore
X:24699423:A:AG	acceptor_gain	1.0000
X:24699424:G:GA	acceptor_gain	1.0000
X:24699424:GC:G	acceptor_gain	1.0000
X:24699424:GCT:G	acceptor_gain	1.0000
X:24699424:GCTC:G	acceptor_gain	1.0000
X:24699424:GCTCT:G	acceptor_gain	1.0000
X:24699545:ATGAA:A	donor_gain	1.0000
X:24699546:TGAA:T	donor_gain	1.0000
X:24699547:GAA:G	donor_gain	1.0000
X:24699547:GAAG:G	donor_gain	1.0000
X:24699548:AA:A	donor_gain	1.0000
X:24699550:GTA:G	donor_loss	1.0000
X:24699550:GTAA:G	donor_gain	1.0000
X:24699551:T:G	donor_loss	1.0000
X:24703241:ATAAT:A	acceptor_gain	1.0000
X:24703344:GATG:G	donor_gain	1.0000
X:24703348:G:GG	donor_gain	1.0000
X:24703349:T:G	donor_loss	1.0000
X:24704384:TGCAG:T	acceptor_loss	1.0000
X:24704385:GCAGA:G	acceptor_loss	1.0000
X:24704386:CAG:C	acceptor_loss	1.0000
X:24704387:A:AG	acceptor_gain	1.0000
X:24704387:AGA:A	acceptor_loss	1.0000
X:24704387:AGAT:A	acceptor_gain	1.0000
X:24704387:AGATG:A	acceptor_gain	1.0000
X:24704388:G:GT	acceptor_gain	1.0000
X:24704388:GA:G	acceptor_gain	1.0000
X:24704388:GAT:G	acceptor_gain	1.0000
X:24704388:GATG:G	acceptor_gain	1.0000
X:24704388:GATGG:G	acceptor_gain	1.0000

AlphaMissense

9759 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:24741494:G:A	G773E	1.000
X:24742032:C:A	R787S	1.000
X:24742033:G:C	R787P	1.000
X:24742037:C:A	N788K	1.000
X:24742037:C:G	N788K	1.000
X:24742048:T:C	L792S	1.000
X:24742051:T:C	L793P	1.000
X:24743303:G:A	G841E	1.000
X:24743312:T:A	V844D	1.000
X:24745442:T:C	L858P	1.000
X:24745445:T:C	L859P	1.000
X:24745447:G:C	D860H	1.000
X:24745448:A:C	D860A	1.000
X:24745448:A:G	D860G	1.000
X:24745448:A:T	D860V	1.000
X:24745450:T:C	F861L	1.000
X:24745452:C:A	F861L	1.000
X:24745452:C:G	F861L	1.000
X:24745456:A:C	S863R	1.000
X:24745458:T:A	S863R	1.000
X:24745458:T:G	S863R	1.000
X:24745460:T:A	L864Q	1.000
X:24745460:T:C	L864P	1.000
X:24745462:T:C	Y865H	1.000
X:24745466:C:A	P866H	1.000
X:24745466:C:G	P866R	1.000
X:24745468:T:C	S867P	1.000
X:24745469:C:T	S867F	1.000
X:24745472:T:A	I868N	1.000
X:24745475:T:A	I869N	1.000

dbSNP variants (sampled 300 via entrez): RS1000011455 (X:24820446 A>G), RS1000021655 (X:24759534 T>A), RS1000040035 (X:24765825 G>C), RS1000081341 (X:24707308 C>G), RS1000100733 (X:24912390 C>A,T), RS1000115113 (X:24892290 A>G), RS1000121299 (X:24910405 G>A), RS1000132896 (X:24983795 G>A,T), RS1000146426 (X:24754479 C>T), RS1000164849 (X:24883110 C>T), RS1000169331 (X:24888925 A>C), RS1000173743 (X:24778976 G>A), RS1000176040 (X:24844135 C>T), RS1000178509 (X:24809240 G>A), RS1000235655 (X:24718778 C>G)

Disease associations

OMIM: gene MIM:312040 | disease phenotypes: MIM:301030, MIM:301220, MIM:601495, MIM:617238

GenCC curated gene-disease

Disease	Classification	Inheritance
X-linked intellectual disability, van Esch type	Definitive	X-linked
X-linked reticulate pigmentary disorder	Strong	X-linked

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
X-linked reticulate pigmentary disorder	Moderate	XL

Mondo (6): X-linked intellectual disability, van Esch type (MONDO:0015601), X-linked reticulate pigmentary disorder (MONDO:0010523), congenital heart disease (MONDO:0005453), inherited aplastic anemia (MONDO:0001713), agammaglobulinemia (MONDO:0015977), myopia 25, autosomal dominant (MONDO:0014982)

Orphanet (5): X-linked intellectual disability, Van Esch type (Orphanet:163976), X-linked reticulate pigmentary disorder (Orphanet:85453), Rare constitutional aplastic anemia (Orphanet:68383), Agammaglobulinemia (Orphanet:183669), Hereditary isolated aplastic anemia (Orphanet:397692)

HPO phenotypes

83 total (30 of 83 shown, HPO-id order):

HPO	Term
HP:0000026	Male hypogonadism
HP:0000028	Cryptorchidism
HP:0000044	Hypogonadotropic hypogonadism
HP:0000154	Wide mouth
HP:0000193	Bifid uvula
HP:0000252	Microcephaly
HP:0000276	Long face
HP:0000278	Retrognathia
HP:0000411	Protruding ear
HP:0000505	Visual impairment
HP:0000559	Corneal scarring
HP:0000565	Esotropia
HP:0000572	Visual loss
HP:0000582	Upslanted palpebral fissure
HP:0000586	Shallow orbits
HP:0000613	Photophobia
HP:0000729	Autistic behavior
HP:0000733	Motor stereotypy
HP:0000815	Hypergonadotropic hypogonadism
HP:0000817	Reduced eye contact
HP:0000837	Increased circulating gonadotropin level
HP:0000960	Sacral dimple
HP:0000962	Hyperkeratosis
HP:0000965	Cutis marmorata
HP:0000966	Hypohidrosis
HP:0001217	Clubbing
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001256	Mild intellectual disability

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST90002395_630	Mean platelet volume	2.000000e-21
GCST90002402_509	Platelet count	6.000000e-10

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004309	platelet count

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D000361	Agammaglobulinemia	C15.378.147.142; C15.604.515.032; C20.673.088
D029502	Anemia, Hypoplastic, Congenital	C15.378.050.085.080; C15.378.190.223.500.500; C16.320.077
D006330	Heart Defects, Congenital	C14.240.400; C14.280.400; C16.131.240.400
C564461	Pigmentary Disorder, Reticulate, with Systemic Manifestations (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL1828 (SINGLE PROTEIN), CHEMBL2363042 (PROTEIN FAMILY)

Molecules with ChEMBL bioactivity

3 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 94,785 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1173055	RUCAPARIB	4	7,009
CHEMBL922	ADEFOVIR DIPIVOXIL	4	27,632
CHEMBL165	RESVERATROL	3	60,144

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

ChEMBL bioactivities

49 potent at pChembl≥5 of 83 total, top 48 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.40	IC50	0.4	nM	RUCAPARIB
9.00	Ki	1	nM	CHEMBL3144215
7.82	IC50	15	nM	CHEMBL483492
6.77	IC50	170	nM	CHEMBL2092833
6.32	IC50	480	nM	CHEMBL2092833
6.17	IC50	680	nM	CHEMBL5281189
6.10	IC50	800	nM	CHEMBL2092835
6.08	Ki	830	nM	DIGALLIC ACID
6.00	IC50	1000	nM	THYMIDINE_TRIPHOSPHATE
6.00	Ki	1000	nM	CHEMBL278903
6.00	EC50	1000	nM	CHEMBL333948
5.93	Ki	1180	nM	ADEFOVIR DIPIVOXIL
5.85	Ki	1400	nM	CHEMBL16119
5.72	IC50	1900	nM	CHEMBL380892
5.72	IC50	1900	nM	CHEMBL210047
5.70	IC50	2000	nM	CHEMBL483492
5.70	EC50	2000	nM	APHIDICOLIN
5.64	Ki	2300	nM	CHEMBL2115349
5.64	IC50	2300	nM	CHEMBL449712
5.62	IC50	2400	nM	APHIDICOLIN
5.60	IC50	2500	nM	CHEMBL1652467
5.58	IC50	2600	nM	APHIDICOLIN
5.58	Ki	2600	nM	CHEMBL16103
5.52	IC50	3000	nM	CHEMBL3126408
5.52	IC50	3000	nM	APHIDICOLIN
5.52	EC50	3000	nM	CHEMBL119903
5.52	EC50	3000	nM	CHEMBL331536
5.48	IC50	3300	nM	CHEMBL210096
5.48	IC50	3300	nM	RESVERATROL
5.46	IC50	3500	nM	CHEMBL380026
5.43	Ki	3750	nM	CHEMBL189703
5.43	IC50	3700	nM	E-ENEDIONE
5.40	EC50	4000	nM	CHEMBL119540
5.40	EC50	4000	nM	CHEMBL118808
5.37	IC50	4300	nM	UNTENONE A
5.37	IC50	4300	nM	APHIDICOLIN
5.30	IC50	5000	nM	CHEMBL1092799
5.30	IC50	5000	nM	CHEMBL1077295
5.30	Ki	5000	nM	CHEMBL278248
5.30	EC50	5000	nM	CHEMBL440899
5.16	IC50	6900	nM	CHEMBL207651
5.16	EC50	7000	nM	CHEMBL332188
5.12	Ki	7500	nM	CHEMBL16193
5.11	Ki	7840	nM	CHEMBL354794
5.10	IC50	8000	nM	CHEMBL364611
5.10	IC50	7900	nM	CHEMBL381375
5.10	EC50	8000	nM	CHEMBL119855
5.05	IC50	8900	nM	CHEMBL437883

PubChem BioAssay actives

49 with measured affinity, of 248 total; 42 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
Rucaparib	1993643: Inhibition of DNA polymerase alpha (unknown origin)	ic50	0.0004	uM
[[(2R,3S,5R)-5-[2-(4-butylphenyl)imino-6-oxo-5H-purin-9-yl]-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate	53664: Compound was tested for its inhibitory activity against HeLa DNA polymerase alpha, Ki values were obtained in the absence of dGTP	ki	0.0010	uM
[[(2S,3R,5S)-5-(4-amino-5-methyl-2-oxopyrimidin-1-yl)-3-fluorooxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate	53475: Compound was evaluated for 50% inhibition of DHBV DNA polymerase (duck hepatitis B virus)	ic50	0.0150	uM
[[(2S,3R,5S)-3-fluoro-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate	53475: Compound was evaluated for 50% inhibition of DHBV DNA polymerase (duck hepatitis B virus)	ic50	0.1700	uM
(1’-acetyloxy-6-methoxy-4’-methyl-3,6’-dioxospiro[2-benzofuran-1,3’-cyclohexa-1,4-diene]-4-yl) acetate	1927528: Inhibition of DNA polymerase alpha (unknown origin)	ic50	0.6800	uM
[[(2S,3R,5S)-5-(4-amino-2-oxopyrimidin-1-yl)-3-fluorooxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate	53475: Compound was evaluated for 50% inhibition of DHBV DNA polymerase (duck hepatitis B virus)	ic50	0.8000	uM
3,4-dihydroxy-5-(3,4,5-trihydroxybenzoyl)oxybenzoic acid	397113: Inhibition of DNA polymerase alpha from human KB3 cells	ki	0.8300	uM
(1R,4aS,10aR)-6-methoxy-1,4a-dimethyl-2,3,4,9,10,10a-hexahydrophenanthren-1-amine	53667: Effective concentration against DNA polymerase alpha	ec50	1.0000	uM
N-(4-butylphenyl)-6-methylsulfanyl-7H-purin-2-amine	53658: Compound was evaluated for the concentration which gives half-maximal inhibition of Chinese Hamster Ovary DNA polymerase alpha	ki	1.0000	uM
[[(2R,3S,4R,5R)-3,4-dihydroxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate	53475: Compound was evaluated for 50% inhibition of DHBV DNA polymerase (duck hepatitis B virus)	ic50	1.0000	uM
Adefovir Dipivoxil	2095787: Binding affinity to DNA polymerase alpha (unknown origin) assessed as inhibition constant	ki	1.1800	uM
N-(4-butylphenyl)-6-methoxy-7H-purin-2-amine	53658: Compound was evaluated for the concentration which gives half-maximal inhibition of Chinese Hamster Ovary DNA polymerase alpha	ki	1.4000	uM
(3aS,4S,7R,7aR)-1,6-dihexadecyl-2,7-bis(methoxycarbonyl)-3-oxo-3a,4,7,7a-tetrahydroindene-4-carboxylic acid	265076: Inhibition of DNA polymerase alpha	ic50	1.9000	uM
(3aS,4S,7R,7aR)-1,6-didodecyl-2,7-bis(methoxycarbonyl)-3-oxo-3a,4,7,7a-tetrahydroindene-4-carboxylic acid	265076: Inhibition of DNA polymerase alpha	ic50	1.9000	uM
(1S,2S,5R,6R,7R,10S,12R,13R)-6,13-bis(hydroxymethyl)-2,6-dimethyltetracyclo[10.3.1.01,10.02,7]hexadecane-5,13-diol	53667: Effective concentration against DNA polymerase alpha	ec50	2.0000	uM
2-(4-butylanilino)-9-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-1H-purin-6-one	53664: Compound was tested for its inhibitory activity against HeLa DNA polymerase alpha, Ki values were obtained in the absence of dGTP	ki	2.3000	uM
7-O-ethyl 2-O,4-O-dimethyl (3aR,4R,7S,7aS)-3,5-dihexadecyl-1-oxo-3a,4,7,7a-tetrahydroindene-2,4,7-tricarboxylate	265076: Inhibition of DNA polymerase alpha	ic50	2.3000	uM
2-(2-amino-6-oxo-1H-purin-9-yl)ethoxymethyl-[hydroxy(phosphonooxy)phosphoryl]oxyphosphinic acid	560428: Inhibition of human DNA polymerase alpha by microplate reader analysis	ic50	2.5000	uM
N-(4-butylphenyl)-6-chloro-7H-purin-2-amine	53658: Compound was evaluated for the concentration which gives half-maximal inhibition of Chinese Hamster Ovary DNA polymerase alpha	ki	2.6000	uM
methyl (1R,4aS,10aR)-7-formyl-6-methoxy-1,4a-dimethyl-2,3,4,9,10,10a-hexahydrophenanthrene-1-carboxylate	53667: Effective concentration against DNA polymerase alpha	ec50	3.0000	uM
[(4bS,8R,8aR)-8-(hydroxymethyl)-3-methoxy-4b,8-dimethyl-5,6,7,8a,9,10-hexahydrophenanthren-2-yl]methanol	53667: Effective concentration against DNA polymerase alpha	ec50	3.0000	uM
(3S,6Z,8E,11S)-3-[(1E,3E,5E)-7-(dimethylamino)-2,5-dimethylhepta-1,3,5-trienyl]-9,11-dimethyl-4,12-dioxa-20-thia-21-azabicyclo[16.2.1]henicosa-1(21),6,8,18-tetraene-5,13-dione	1073657: Inhibition of DNA polymerase-alpha (unknown origin) assessed as incorporation of Br(d)UTP by colorimetric analysis	ic50	3.0000	uM
(3aS,4S,7R,7aR)-1,6-dihexadecyl-3-oxo-2,7-bis(propan-2-yloxycarbonyl)-3a,4,7,7a-tetrahydroindene-4-carboxylic acid	265076: Inhibition of DNA polymerase alpha	ic50	3.3000	uM
Resveratrol	1662436: Inhibition of human DNA polymerase-alpha (unknown origin)	ic50	3.3000	uM
7-O-ethyl 2-O,4-O-dimethyl (3aR,4S,7S,7aS)-3,5-dihexadecyl-1-oxo-3a,4,7,7a-tetrahydroindene-2,4,7-tricarboxylate	265076: Inhibition of DNA polymerase alpha	ic50	3.5000	uM
methyl (E)-3,6-dioxodocos-4-enoate	265076: Inhibition of DNA polymerase alpha	ic50	3.7000	uM
2-[[(3S,10R,13R,17R)-10,13-dimethyl-17-[(2R)-6-methylheptan-2-yl]-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl]oxy]acetic acid	239315: Inhibition constant against DNA polymerase alpha non competitively on dNTP substrate	ki	3.7500	uM
(1R,2R,4aS,10aR)-1,7-bis(hydroxymethyl)-1,4a-dimethyl-2,3,4,9,10,10a-hexahydrophenanthrene-2,6-diol	53667: Effective concentration against DNA polymerase alpha	ec50	4.0000	uM
(1R,4aS,10aR)-6-methoxy-1,4a-dimethyl-2,3,4,9,10,10a-hexahydrophenanthrene-1-carboxylic acid	53667: Effective concentration against DNA polymerase alpha	ec50	4.0000	uM
methyl (1S,2S)-2-hexadecyl-2-hydroxy-5-oxocyclopent-3-ene-1-carboxylate	265076: Inhibition of DNA polymerase alpha	ic50	4.3000	uM
(1R,4aS,10aR)-7-formyl-6-hydroxy-1,4a-dimethyl-2,3,4,9,10,10a-hexahydrophenanthrene-1-carboxylic acid	53667: Effective concentration against DNA polymerase alpha	ec50	5.0000	uM
N-(4-butylphenyl)-7H-purin-2-amine	53658: Compound was evaluated for the concentration which gives half-maximal inhibition of Chinese Hamster Ovary DNA polymerase alpha	ki	5.0000	uM
N-[(4-chlorophenyl)methyl]-4-methyl-7-(morpholin-4-ylmethyl)-3,10-dioxo-1,4-diazatricyclo[7.3.1.05,13]trideca-5,7,9(13),11-tetraene-11-carboxamide	464101: Inhibition of human recombinant DNA polymerase alpha expressed in baculovirus infected SF9 cells after 12 mins by scintillation proximity assay	ic50	5.0000	uM
7-[[[(2R)-2-(1-benzofuran-2-yl)-2-hydroxyethyl]-methylamino]methyl]-N-[(4-chlorophenyl)methyl]-4-methyl-3,10-dioxo-1,4-diazatricyclo[7.3.1.05,13]trideca-5,7,9(13),11-tetraene-11-carboxamide	464101: Inhibition of human recombinant DNA polymerase alpha expressed in baculovirus infected SF9 cells after 12 mins by scintillation proximity assay	ic50	5.0000	uM
dimethyl (3aR,4R,7S,7aS)-3,5-dihexadecyl-1-oxo-7-(2-phenylethylcarbamoyl)-3a,4,7,7a-tetrahydroindene-2,4-dicarboxylate	265076: Inhibition of DNA polymerase alpha	ic50	6.9000	uM
(1R,2S,4aS,10aR)-1,7-bis(hydroxymethyl)-1,4a-dimethyl-2,3,4,9,10,10a-hexahydrophenanthrene-2,6-diol	53667: Effective concentration against DNA polymerase alpha	ec50	7.0000	uM
2-(4-butylanilino)-1,7-dihydropurin-6-one	53664: Compound was tested for its inhibitory activity against HeLa DNA polymerase alpha, Ki values were obtained in the absence of dGTP	ki	7.5000	uM
2-[[(3S,5S,8R,9S,10S,13R,14S,17R)-10,13-dimethyl-17-[(2R)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl]oxy]acetic acid	239315: Inhibition constant against DNA polymerase alpha non competitively on dNTP substrate	ki	7.8400	uM
methyl (2R,3S,4R,5E)-4-hydroxy-5-(2-oxononadecylidene)-2-phenyl-1-(2-phenylethyl)pyrrolidine-3-carboxylate	265076: Inhibition of DNA polymerase alpha	ic50	7.9000	uM
(1R,2R,4aS,10aR)-1-(hydroxymethyl)-1,4a-dimethyl-2,3,4,9,10,10a-hexahydrophenanthrene-2,6-diol	53667: Effective concentration against DNA polymerase alpha	ec50	8.0000	uM
2-[[(3S,10R,13R,17R)-17-[(E,2R,5S)-5-ethyl-6-methylhept-3-en-2-yl]-10,13-dimethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl]oxy]acetic acid	242140: Inhibitory concentration against human DNA polymerase alpha incubated with 0.05 units	ic50	8.0000	uM
methyl (2S,3S,4R,5E)-2-ethyl-4-hydroxy-5-(2-oxononadecylidene)-1-(2-phenylethyl)pyrrolidine-3-carboxylate	265076: Inhibition of DNA polymerase alpha	ic50	8.9000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases methylation, affects methylation, decreases expression, decreases methylation, increases expression	7
Resveratrol	affects cotreatment, increases expression, decreases expression	3
Cisplatin	decreases expression, increases reaction, increases expression, increases response to substance	3
Cadmium Chloride	decreases expression, increases abundance, increases expression	3
bisphenol A	decreases expression, decreases methylation	2
sodium arsenite	decreases expression, affects cotreatment, increases abundance	2
chromium hexavalent ion	increases expression, decreases expression, increases abundance	2
Rotenone	decreases expression, increases expression	2
Valproic Acid	decreases methylation, affects expression	2
Cyclosporine	decreases expression	2
Aflatoxin B1	affects expression, decreases methylation	2
aristolochic acid I	decreases expression	1
GSK-J4	decreases expression	1
FR900359	decreases phosphorylation	1
bisphenol F	affects cotreatment, increases expression	1
triphenyl phosphate	affects expression	1
geraniol	decreases expression	1
2,2’-methylenebis(4-methyl-6-tert-butylphenol)	affects expression, affects response to substance	1
methylselenic acid	decreases expression	1
sodium arsenate	decreases expression	1
arsenite	decreases reaction, affects binding	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cobaltous chloride	decreases expression	1
zinc chromate	decreases expression, increases abundance	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
potassium chromate(VI)	increases expression	1
cadmium acetate	decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
1-nitropyrene	increases expression	1
beta-methylcholine	affects expression	1

ChEMBL screening assays

73 unique, capped per target: 64 binding, 5 admet, 4 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1000068	Binding	Inhibition of human DNA polymerase alpha	Anti-AIDS agents, 1. Isolation and characterization of four new tetragalloylquinic acids as a new class of HIV reverse transcriptase inhibitors from tannic acid. — J Nat Prod
CHEMBL4008260	ADMET	Inhibition of recombinant human DNA polymerase alpha preincubated with enzyme followed by addition of dATP/dGTP/TTP as substrate in presence of [gamma-33P]TTP by phosphorimaging assay	Discovery and Synthesis of a Phosphoramidate Prodrug of a Pyrrolo[2,1-f][triazin-4-amino] Adenine C-Nucleoside (GS-5734) for the Treatment of Ebola and Emerging Viruses. — J Med Chem
CHEMBL6194221	Functional	Inhibition of human POLA1 using DNA-dependant DNA polymerase activity assay (POLA1) ( DNA polymerase alpha (CHIMERx))	Data for DCP probe JNJ-8003

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00668824	PHASE4	UNKNOWN	Improved Diagnosis of Congenital Heart Disease by Magnetic Resonance Imaging Using Vasovist
NCT01368705	PHASE4	COMPLETED	Nitrogen Balance in Infants After Post Cardiothoracic Surgery
NCT01619982	PHASE4	COMPLETED	Pre-operative Prophylaxis With Vancomycin and Cefazolin in Pediatric Cardiovascular Surgery Patients
NCT02122679	PHASE4	WITHDRAWN	Tranexamic Acid Effect on Platelet Aggregation Following Infant Cardiopulmonary Bypass
NCT02527811	PHASE4	UNKNOWN	Ulinastatin Injection in in Pediatric Patients Undergoing Open Heart Surgery
NCT03014700	PHASE4	COMPLETED	Fibrinogen Concentrate vs Cryoprecipitate
NCT03408340	PHASE4	TERMINATED	Paravertebral Nerve Blocks in Neonates
NCT03630796	PHASE4	UNKNOWN	Effect of Sevoflurane in Postoperative Troponin I Levels in Children Undergoing Congenital Heart Defects Surgery
NCT03667703	PHASE4	COMPLETED	Stress Ulcer Prophylaxis Versus Placebo in Critically Ill Infants With Congenital Heart Disease
NCT04453761	PHASE4	UNKNOWN	Thiamine Influenced on Substrate Energy Effectiveness in Indonesian Children Undergoing Cardiopulmonary Bypass
NCT06668389	PHASE4	RECRUITING	Sodium-Glucose Cotransporter 2 Inhibitors for Repaired Tetralogy of Fallot Patients for Enhancement of Cardio-Pulmonary Status Trial
NCT07499154	PHASE4	NOT_YET_RECRUITING	Perioperative Lidocaine for Lung Protection in Infants Undergoing Cardiac Surgery
NCT00000470	PHASE3	COMPLETED	Infant Heart Surgery: Central Nervous System Sequelae of Circulatory Arrest
NCT00000494	PHASE3	COMPLETED	Management of Patent Ductus in Premature Infants
NCT01134302	PHASE3	UNKNOWN	Hybrid Versus Norwood Management Strategies in Infants Undergoing Single Ventricle Palliation
NCT01607983	PHASE3	WITHDRAWN	Effects of Pulmonary Vasodilation Upon VA Coupling in Fontan Patients
NCT01662011	PHASE3	UNKNOWN	Application of Neurally Adjusted Ventilatory Assist to Children After Congenital Cardiac Surgery
NCT02320669	PHASE3	COMPLETED	Phase 3 Triiodothyronine Supplementation for Infants After Cardiopulmonary Bypass
NCT02615262	PHASE3	COMPLETED	Intraoperative Dexamethasone in Pediatric Cardiac Surgery
NCT03153137	PHASE3	COMPLETED	Clinical Study Assessing the Efficacy and Safety of Macitentan in Fontan-palliated Subjects
NCT03154476	PHASE3	COMPLETED	Role of Sildenafil for Fontan Associated Liver Disease (SiFALD) Study
NCT04536194	PHASE3	COMPLETED	Dopamine Versus Norepinephrine Under General Anesthesia
NCT04702373	PHASE3	ACTIVE_NOT_RECRUITING	Training in Exercise Activities and Motion for Growth (TEAM 4 Growth) RCT
NCT05049590	PHASE3	COMPLETED	Acute Normovolemic Hemodilution in Complex Cardiac Surgery
NCT06406517	PHASE3	UNKNOWN	Comparative Effectiveness of Gadopiclenol for Evaluation of Adult Congenital Heart Anatomy and Hemodynamics
NCT06693674	PHASE3	RECRUITING	Effect of Sacubitril-Valsartan on Cardiac Structure and Function
NCT06955260	PHASE3	NOT_YET_RECRUITING	SGLT2 Inhibition With Empagliflozin in Fontan Circulatory Failure
NCT00115375	PHASE2	COMPLETED	Platelet Aggregation Inhibition in Children on Clopidogrel (PICOLO)
NCT00350220	PHASE2	COMPLETED	Transfusion Strategies in Pediatric Cardiothoracic Surgery
NCT00374088	PHASE2	COMPLETED	N-Acetylcysteine in Neonatal Congenital Heart Surgery (INACT Study)
NCT00538785	PHASE2	COMPLETED	A Study to Evaluate MEDI-524 In Children With Hemodynamically Significant Congenital Heart Disease
NCT00770705	PHASE2	WITHDRAWN	Parenteral Phenoxybenzamine During Congenital Heart Disease Surgery
NCT00919945	PHASE2	TERMINATED	Impact of Early Enteral Feeding on Splanchnic Blood Flow After Surgery for Critical Heart Disease in the Newborn
NCT01063712	PHASE2	COMPLETED	Safety and Effectiveness of the Device Nit-Occlud® PDA-R
NCT01069510	PHASE2	COMPLETED	Spironolactone in Adult Congenital Heart Disease
NCT01189981	PHASE2	COMPLETED	Effect of eHealth Encouragements to Intensive Exercise in Adolescents With Congenital Heart Disease
NCT01330433	PHASE2	COMPLETED	Effects of CoSeal on Bleeding & Adhesions in Pediatric Heart Surgery
NCT01662037	PHASE2	COMPLETED	Bosentan Therapy in Children With Functional Single Ventricle
NCT01668264	PHASE2	UNKNOWN	Imaging Assessment of Diastolic Function
NCT01827059	PHASE2	UNKNOWN	Bosentan In Exercise Induced Pulmonary Arterial Hypertension in CongenitaL Heart diseasE