PRIM2

Summary

PRIM2 (DNA primase subunit 2, HGNC:9370) is a protein-coding gene on chromosome 6p11.2, encoding DNA primase large subunit (P49643). Regulatory subunit of the DNA primase complex and component of the DNA polymerase alpha complex (also known as the alpha DNA polymerase-primase complex) which play an essential role in the initiation of DNA synthesis. It is a common-essential gene (DepMap: required in 100.0% of cancer cell lines).

This gene encodes the 58 kilodalton subunit of DNA primase, an enzyme that plays a key role in the replication of DNA. The encoded protein forms a heterodimer with a 49 kilodalton subunit. This heterodimer functions as a DNA-directed RNA polymerase to synthesize small RNA primers that are used to create Okazaki fragments on the lagging strand of the DNA. Alternative splicing of this gene results in multiple transcript variants. This gene has a related pseudogene, which is also present on chromosome 6.

Source: NCBI Gene 5558 — RefSeq curated summary.

At a glance

• GWAS associations: 6
• Clinical variants (ClinVar): 31 total
• Regional missense constraint (gnomAD): 1 of 4 regions constrained (≈5% of expected missense variation)
• GTEx eGene: eQTL in 14 tissues, sQTL in 10 (q < 0.05)
• Cancer dependency (DepMap): dependent in 100.0% of screened cell lines (common-essential)
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.93 (unconstrained)
• MANE Select transcript: NM_000947

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9370
Approved symbol	PRIM2
Name	DNA primase subunit 2
Location	6p11.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000146143
Ensembl biotype	protein_coding
OMIM	176636
Entrez	5558

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 14 protein_coding, 2 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay, 1 retained_intron

MANE Select: ENST00000615550

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

ENST00000615550, ENST00000274891, ENST00000370687, ENST00000419977, ENST00000470638, ENST00000490313, ENST00000550475, ENST00000671770, ENST00000672107, ENST00000934977, ENST00000934978, ENST00000934979, ENST00000934980, ENST00001038972, ENST00001073461, ENST00001104161, ENST00001104162, ENST00001127901, ENST00001137902

RefSeq mRNA: 3 — MANE Select: NM_000947 NM_000947, NM_001282487, NM_001282488

CCDS: CCDS75476, CCDS75477

Canonical transcript exons

ENST00000615550 — 14 exons

Exon	Start	End
ENSE00002425964	57537440	57537625
ENSE00003713374	57606375	57606457
ENSE00003719061	57532411	57532483
ENSE00003719133	57382031	57382168
ENSE00003722747	57645928	57646850
ENSE00003727335	57507387	57507454
ENSE00003734777	57379901	57379996
ENSE00003735385	57632133	57632201
ENSE00003735855	57320457	57320560
ENSE00003738215	57324201	57324280
ENSE00003745149	57325925	57326045
ENSE00003749833	57601093	57601219
ENSE00003751924	57318437	57318599
ENSE00003844426	57317630	57317701

Expression profiles

Bgee: expression breadth ubiquitous, 179 present calls, max score 92.93.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 25.6502 / max 842.0722, expressed in 1795 samples.

Highest expression (Bgee): buccal mucosa cell, primordial germ cell in gonad, ganglionic eminence, calcaneal tendon, ventricular zone.

Genetic regulation across tissues (GTEx eQTL / sQTL)

PRIM2 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 14 tissues and its splicing (sQTL) in 10 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 24 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Muscle Skeletal	eqtl	3.9e-34	-0.41	6:57646338:A:G
Artery Tibial	sqtl	3.2e-25	-0.90	6:57532411:T:C
Skin Sun Exposed Lower leg	sqtl	3.8e-14	-0.67	6:57532411:T:C
Cells Cultured fibroblasts	sqtl	5.5e-10	-0.46	6:57396243:A:G
Prostate	eqtl	7.1e-10	+0.51	6:57341331:A:G
Cells Cultured fibroblasts	eqtl	1.7e-06	-0.13	6:57523696:AG:A
Esophagus Muscularis	eqtl	2.1e-06	-0.23	6:57616995:T:C
Heart Atrial Appendage	eqtl	6.0e-05	-0.28	6:57646338:A:G
Breast Mammary Tissue	sqtl	7.1e-05	+0.53	6:57920818:G:C
Nerve Tibial	sqtl	8.4e-05	+0.45	6:57532411:T:C
Esophagus Gastroesophageal Junction	eqtl	2.2e-04	-0.25	6:57514893:C:T
Cells EBV-transformed lymphocytes	eqtl	4.6e-04	-0.20	6:58107636:T:C
Heart Left Ventricle	eqtl	7.1e-04	-0.23	6:57637463:A:G
Colon Sigmoid	eqtl	1.0e-03	-0.20	6:57641568:C:A
Cells EBV-transformed lymphocytes	sqtl	1.1e-03	-0.53	6:57418933:T:C
Esophagus Mucosa	eqtl	1.7e-03	+0.31	6:57364689:G:A
Colon Transverse	eqtl	3.2e-03	+0.18	6:57456429:C:G
Esophagus Mucosa	sqtl	3.5e-03	-0.32	6:57637463:A:G
Minor Salivary Gland	eqtl	4.4e-03	+0.29	6:57324686:G:T
Skin Sun Exposed Lower leg	eqtl	5.3e-03	-0.43	6:56512915:C:T

FANTOM5 promoters

2 alternative TSS:

Promoter ID	TPM avg	Samples expressed
68338	25.1289	1795
68339	0.5213	252

Top tissues by expression

showing 100 of 283 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	92.93	silver quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.15	gold quality
ganglionic eminence	UBERON:0004023	86.54	gold quality
calcaneal tendon	UBERON:0003701	86.01	gold quality
ventricular zone	UBERON:0003053	85.64	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.93	gold quality
oocyte	CL:0000023	84.75	gold quality
colonic epithelium	UBERON:0000397	82.84	gold quality
stromal cell of endometrium	CL:0002255	81.81	gold quality
cortical plate	UBERON:0005343	80.54	gold quality
rectum	UBERON:0001052	79.97	gold quality
adrenal tissue	UBERON:0018303	79.61	gold quality
sural nerve	UBERON:0015488	78.16	gold quality
mucosa of transverse colon	UBERON:0004991	77.67	gold quality
islet of Langerhans	UBERON:0000006	77.62	gold quality
bone marrow cell	CL:0002092	77.49	gold quality
leukocyte	CL:0000738	77.39	gold quality
monocyte	CL:0000576	77.14	gold quality
mononuclear cell	CL:0000842	77.05	gold quality
lymph node	UBERON:0000029	76.82	gold quality
body of uterus	UBERON:0009853	76.62	gold quality
granulocyte	CL:0000094	76.47	gold quality
smooth muscle tissue	UBERON:0001135	76.37	gold quality
tibial artery	UBERON:0007610	76.21	gold quality
popliteal artery	UBERON:0002250	76.20	gold quality
muscle layer of sigmoid colon	UBERON:0035805	75.66	gold quality
ectocervix	UBERON:0012249	75.60	gold quality
transverse colon	UBERON:0001157	75.47	gold quality
aorta	UBERON:0000947	75.44	gold quality
prostate gland	UBERON:0002367	75.09	gold quality
skin of leg	UBERON:0001511	75.07	gold quality
bone marrow	UBERON:0002371	74.89	gold quality
descending thoracic aorta	UBERON:0002345	74.83	gold quality
thoracic aorta	UBERON:0001515	74.72	gold quality
skin of abdomen	UBERON:0001416	74.71	gold quality
left ovary	UBERON:0002119	74.71	gold quality
ascending aorta	UBERON:0001496	74.60	gold quality
tendon	UBERON:0000043	74.58	gold quality
endocervix	UBERON:0000458	74.38	gold quality
lower esophagus	UBERON:0013473	74.25	gold quality
lower esophagus muscularis layer	UBERON:0035833	74.25	gold quality
esophagus	UBERON:0001043	74.23	gold quality
right ovary	UBERON:0002118	74.22	gold quality
vermiform appendix	UBERON:0001154	74.20	gold quality
esophagus mucosa	UBERON:0002469	74.12	gold quality
stomach	UBERON:0000945	74.02	gold quality
right uterine tube	UBERON:0001302	73.99	gold quality
pancreas	UBERON:0001264	73.89	gold quality
right coronary artery	UBERON:0001625	73.87	gold quality
body of stomach	UBERON:0001161	73.80	gold quality
body of pancreas	UBERON:0001150	73.79	gold quality
gall bladder	UBERON:0002110	73.78	gold quality
left uterine tube	UBERON:0001303	73.74	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	73.74	gold quality
left coronary artery	UBERON:0001626	73.66	gold quality
small intestine Peyer’s patch	UBERON:0003454	73.66	gold quality
spleen	UBERON:0002106	73.65	gold quality
tonsil	UBERON:0002372	73.51	gold quality
omental fat pad	UBERON:0010414	73.38	gold quality
peritoneum	UBERON:0002358	73.33	gold quality
right adrenal gland cortex	UBERON:0035827	73.31	gold quality
minor salivary gland	UBERON:0001830	73.20	gold quality
right adrenal gland	UBERON:0001233	73.07	gold quality
colon	UBERON:0001155	72.84	gold quality
left adrenal gland	UBERON:0001234	72.84	gold quality
intestine	UBERON:0000160	72.82	gold quality
adrenal gland	UBERON:0002369	72.71	gold quality
right lung	UBERON:0002167	72.70	gold quality
large intestine	UBERON:0000059	72.66	gold quality
hindlimb stylopod muscle	UBERON:0004252	72.65	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	72.64	gold quality
coronary artery	UBERON:0001621	72.63	gold quality
metanephros cortex	UBERON:0010533	72.46	gold quality
adipose tissue of abdominal region	UBERON:0007808	72.38	gold quality
nerve	UBERON:0001021	72.37	gold quality
tibial nerve	UBERON:0001323	72.37	gold quality
left adrenal gland cortex	UBERON:0035825	72.29	gold quality
small intestine	UBERON:0002108	72.28	gold quality
embryo	UBERON:0000922	72.14	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	71.91	gold quality
upper lobe of left lung	UBERON:0008952	71.68	gold quality
zone of skin	UBERON:0000014	71.64	gold quality
left lobe of thyroid gland	UBERON:0001120	71.39	gold quality
adrenal cortex	UBERON:0001235	71.33	gold quality
saliva-secreting gland	UBERON:0001044	71.32	gold quality
right atrium auricular region	UBERON:0006631	71.24	gold quality
right lobe of thyroid gland	UBERON:0001119	71.15	gold quality
caecum	UBERON:0001153	71.09	gold quality
muscle of leg	UBERON:0001383	71.01	gold quality
upper lobe of lung	UBERON:0008948	71.00	gold quality
gastrocnemius	UBERON:0001388	70.79	gold quality
ovary	UBERON:0000992	70.75	gold quality
uterine cervix	UBERON:0000002	70.69	gold quality
blood	UBERON:0000178	70.56	gold quality
thyroid gland	UBERON:0002046	70.51	gold quality
secondary oocyte	CL:0000655	70.39	gold quality
mouth mucosa	UBERON:0003729	70.34	gold quality
mucosa of stomach	UBERON:0001199	70.32	gold quality
subcutaneous adipose tissue	UBERON:0002190	70.32	gold quality
vagina	UBERON:0000996	69.98	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.33

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 76 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM
Prostate	tissue	30.3
Choroid plexus	tissue	30.2
Thymus	tissue	14.9
Hippocampus	tissue	14.4
Bone marrow	tissue	14.4
Nucleus accumbens	tissue	12.5
Locus coeruleus	tissue	11.8
Hippocampal formation	tissue	11.7
Tonsil	tissue	11.2
Prefrontal cortex	tissue	11.1
Cerebral cortex	tissue	11.1
Entorhinal cortex	tissue	11.1
Temporal cortex	tissue	10.5
Occipital cortex	tissue	10.2
Lymph node	tissue	10.0
Postcentral gyrus	tissue	9.7
Retrosplenial and cingulate cortex	tissue	8.2
Rectum	tissue	8.0
Amygdala	tissue	8.0
Somatosensory cortex	tissue	8.0
Motor cortex	tissue	7.6
Cerebellum	tissue	7.6
Smooth muscle	tissue	7.5
Retrosplenial cortex	tissue	7.5
Ovary	tissue	7.4
Insular cortex	tissue	7.4
Caudate putamen	tissue	7.2
Placenta	tissue	7.1
Endometrium 1	tissue	7.0
Frontal cortex	tissue	7.0
Breast	tissue	6.8
Colon	tissue	6.6
Olfactory bulb	tissue	6.4
Appendix	tissue	6.4
Testis	tissue	6.3
Epididymis	tissue	6.3
Pons	tissue	6.2
Basal ganglia	tissue	6.2
Midbrain	tissue	6.2
Septum	tissue	6.1
Fallopian tube	tissue	6.0
Ventral forebrain	tissue	5.9
Skin 1	tissue	5.8
Hypothalamus	tissue	5.8
Substantia nigra	tissue	5.8
Urinary bladder	tissue	5.7
Superior colliculi	tissue	5.7
Spinal cord	tissue	5.7
Cervix	tissue	5.6
Thalamus	tissue	5.6
Duodenum	tissue	5.6
Seminal vesicle	tissue	5.5
Periaqueductal gray	tissue	5.5
Putamen	tissue	5.4
Spleen	tissue	5.4
Medulla oblongata	tissue	5.1
Small intestine	tissue	5.1
Liver	tissue	4.8
Corpus callosum	tissue	4.8
Lung	tissue	4.7

Brain sub-regions (HPA Brain Atlas): detected in 189; highest nTPM — Somatomor cortex, precentral gyrus (white matter) (43.5), Ventral tegmental area (24.7), Area parastriata, superior (24.4), Mammillary body (23.9), Fusiform gyrus (23.5).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F1, E2F4

miRNA regulators (miRDB)

Targeting PRIM2 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 58 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-8062	99.88	68.43	995
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-489-3P	99.80	66.46	839
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-3913-3P	99.74	66.53	938
HSA-MIR-4677-5P	99.70	70.09	1940
HSA-MIR-30B-3P	99.70	65.76	2325
HSA-MIR-3689A-3P	99.70	65.73	2306
HSA-MIR-3689B-3P	99.70	65.71	2311
HSA-MIR-3689C	99.70	65.71	2311
HSA-MIR-6779-5P	99.70	65.76	2363
HSA-MIR-1283	99.69	72.42	3009
HSA-MIR-4743-3P	99.62	68.12	2095
HSA-MIR-7159-5P	99.53	72.12	2472
HSA-MIR-7106-5P	99.53	67.47	3574
HSA-MIR-3915	99.45	68.49	1905
HSA-MIR-330-3P	99.41	69.95	2521

Functional genomics

gnomAD constraint: pLI 0.000714, LOEUF 0.925, missense Z 1.28 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000615550 splits into 4 regions with different missense tolerance; 1 is missense-constrained (≈5% 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
6:57,318,446–57,324,217	96 / 98.3	0.98	no
6:57,324,218–57,606,457	229 / 383.6	0.60	no
6:57,632,133–57,632,201	1 / 27.3	0.04	yes (p 4.7e-07)
6:57,645,928–57,646,155	72 / 89.4	0.81	no
DepMap (CRISPR cell-line fitness): dependent in 100.0% of screened cell lines, common-essential.

Most-dependent cell lines (DepMap gene-effect, lower = stronger; ≤ −0.5 shown): YCUB-2 (-3.795), C337 (-3.771), NRH-UPS3 (-3.763), NOMO-1 (-3.682), Hs 683 (-3.661), JVE-207 (-3.633), UM-HACC-2A (-3.626), HuO-3N1 (-3.624), KU812 (-3.622), DND-41 (-3.583), NRH-UPS1 (-3.562), ZR-75-1 (-3.53), NCI-H23 (-3.523), MEL-JUSO (-3.521), SK-ES-1 (-3.509).

Literature-anchored findings (GeneRIF, showing 10)

• analysis of the iron-sulfur cluster in the C-terminal domain of the p58 subunit of human DNA primase (PMID:17893144)
• p58C(C-terminal regulatory domain of the large subunit) structure reveals a novel arrangement of an evolutionarily conserved 4Fe-4S cluster buried deeply within the protein core and is not similar to any known protein structure. (PMID:20643958)
• The fragment that forms a beta-sheet in the reported structure p58C/3L9Q of the same human primase domain is folded in three alpha-helices in our p58C/3Q36 structure, similarly to yeast primase. (PMID:21346410)
• PRIM2 gene is not imprinted in the placenta. (PMID:22437878)
• 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)
• Data indicate that the conformational changes in primase are necessary to accomplish the initiation and then elongation of RNA synthesis. (PMID:25550159)
• Data suggest that PRIM1-p58,C-terminal domain stays bound to initiating NTP and 3prime-overhang DNA during whole cycle of RNA primer synthesis; meanwhile, PRIM1-p49 slides along DNA template toward 5prime-end with PRIM1-p58,N-terminal domain attached. (PMID:26710848)
• Study results show that although human DNA primase C-terminal domain (p58C) can be stabilized in different conformations in the crystalline state, in solution there is effectively no difference in the structure and functional properties of p58C constructs of different lengths. (PMID:30562384)
• Genetic variants of CHEK1, PRIM2 and CDK6 in the mitotic phase-related pathway are associated with nonsmall cell lung cancer survival. (PMID:34058013)
• PRIM2: A Marker of MYC-driven Hyper-proliferation, Disease Progression, Tumor Aggressiveness and Poor Survival in Glioma Patients. (PMID:38423596)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	prim2	ENSDARG00000052721
mus_musculus	Prim2	ENSMUSG00000026134
rattus_norvegicus	Prim2	ENSRNOG00000012486
drosophila_melanogaster	Prim2	FBGN0259676
caenorhabditis_elegans	pri-2	WBGENE00004181

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
Thermoplasma volcanium GSS1	Q97BA1	53.8%	Diamond
Schizosaccharomyces pombe 972h-	O74761	45.6%	Diamond
Neurospora crassa OR74A	Q8NIZ4	45.6%	Diamond
Saccharomyces cerevisiae S288C	P20457	44.0%	Diamond
Arabidopsis thaliana	Q84WJ2	41.7%	Diamond
Dictyostelium discoideum	Q55BM5	32.9%	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
MIR548U	ncRNA	100422884
LINC03001	ncRNA	100506188
TRNAI-AAU	tRNA	107986679
TRA-AGC24-1	tRNA	116485204
TRI-AAT1-1	tRNA	100189249
RAB23	protein-coding	51715
BAG2	protein-coding	9532
ZNF451-AS1	ncRNA	101927211
ZNF451	protein-coding	26036
KIAA1586	protein-coding	57691
TRA-AGC13-2	tRNA	100189060

Protein

Protein identifiers

DNA primase large subunit — P49643 (reviewed: P49643)

Alternative names: DNA primase 58 kDa subunit

All UniProt accessions (4): A0A096LP51, A0A5F9ZHR0, A0A5F9ZHU7, P49643

UniProt curated annotations — full annotation on UniProt →

Function. Regulatory subunit of the DNA primase complex and component of the DNA polymerase alpha complex (also known as the alpha DNA polymerase-primase complex) which play 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, an accessory subunit POLA2 and two primase subunits, the catalytic subunit PRIM1 and the regulatory subunit 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. In the primase complex, both subunits are necessary for the initial di-nucleotide formation, but the extension of the primer depends only on the catalytic subunit. Binds RNA:DNA duplex and coordinates the catalytic activities of PRIM1 and POLA2 during primase-to-polymerase switch.

Subunit / interactions. Heterodimer of a catalytic subunit PRIM1 and a regulatory subunit PRIM2, also known as the DNA primase complex. Interacts via (C-terminus) with PRIM1. 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. Within the complex, POLA1 directly interacts with PRIM2.

Cofactor. Binds 1 [4Fe-4S] cluster.

Domain organisation. The RNA:DNA duplex-binding domain interacts with the template phosphates at positions -2, -1, 1, and 2 positioning its bases -1, 1, and 2 for duplex formation. Interacts only with the beta- and gamma-phosphates of triphosphate moiety of initiating NTP of the primer. The side chain of His-303 mimics a RNA base that would be paired with the template nucleotide at position -1 via a hydrogen bond, thereby facilitating the stacking of the initiating NTP. In the initiating primosome a ‘mini RNA:DNA’ duplex is formed comprising three template nucleotides at positions -1, 1, and 2 on one strand and His-303, initiating NTP, and incoming NTP on the other strand. The interdomain linker provides flexibility in movement relative to primosome platform composed of PRIM1, the N-terminus of PRIM2, the C-terminus of POLA1 and POLA2. Together with POLA1 interdomain linker, allows for large-scale conformational changes of primosome and coordinated autoregulation of catalytic centers of PRIM1 and POLA1. It is proposed to move the C-terminus of PRIM2 close to PRIM1 during initiation, then move it away with the 5’-end of the nascent primer during elongation. The steric hindrance between the N- and C-terminus of PRIM2 as the RNA primer is elongated limits its length to 9 nucleotides. Ultimately a large rotation of the C-terminus of PRIM2 transfers the primer to POLA1 active site for DNA synthesis.

Similarity. Belongs to the eukaryotic-type primase large subunit family.

Isoforms (2)

UniProt ID	Names	Canonical?
P49643-1	1	yes
P49643-2	2

RefSeq proteins (3): NP_000938, NP_001269416, NP_001269417 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007238	DNA_primase_lsu_euk/arc	Family
IPR016558	DNA_primase_lsu_euk	Family
IPR058560	DNA_primase_C	Domain

Pfam: PF04104, PF26466

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

UniProt features (68 total): helix 24, strand 12, sequence variant 7, mutagenesis site 5, turn 5, region of interest 4, binding site 4, sequence conflict 3, splice variant 2, chain 1, modified residue 1

Structure

Experimental structures (PDB)

22 structures by resolution:

PDB	Title	Method	Resolution (Å)
3L9Q	Crystal structure of human polymerase alpha-primase p58 iron-sulfur cluster domain	X-RAY DIFFRACTION	1.7
5I7M	Crystal structure of Y345F mutant of human primase p58 iron-sulfur cluster domain	X-RAY DIFFRACTION	1.93
6DHW	Crystal structure of primase iron-sulfur domain (266-457)	X-RAY DIFFRACTION	2.01
5F0Q	Crystal structure of C-terminal domain of the human DNA primase large subunit with bound …	X-RAY DIFFRACTION	2.21
5DQO	Crystal structure of Y347F mutant of human primase p58 iron-sulfur cluster domain	X-RAY DIFFRACTION	2.3
3Q36	Crystal structure of the 4Fe-4S cluster domain of human DNA primase large subunit	X-RAY DIFFRACTION	2.5
4RR2	Crystal structure of human primase	X-RAY DIFFRACTION	2.65
4BPU	Crystal structure of human primase in heterodimeric form, comprising PriS and truncated …	X-RAY DIFFRACTION	2.7
8VY3	Human DNA polymerase alpha/primase - AavLEA1 (1:40 molar ratio)	ELECTRON MICROSCOPY	2.98
5F0S	Crystal structure of C-terminal domain of the human DNA primase large subunit with bound …	X-RAY DIFFRACTION	3
4BPW	Crystal structure of human primase bound to UTP	X-RAY DIFFRACTION	3
8QJ7	Cryo-EM structure of human DNA polymerase alpha-primase in pre-initiation stage 1	ELECTRON MICROSCOPY	3.07
8D96	Human DNA polymerase alpha/primase elongation complex I bound to primer/template	ELECTRON MICROSCOPY	3.35
9C8V	Human DNA polymerase alpha/primase - CHAPSO (4 mM)	ELECTRON MICROSCOPY	3.39
4BPX	Crystal structure of human primase in complex with the primase- binding motif of DNA …	X-RAY DIFFRACTION	3.4
8B9D	Human replisome bound by Pol Alpha	ELECTRON MICROSCOPY	3.4
8D0B	Human CST-DNA polymerase alpha/primase preinitiation complex bound to 4xTEL-foldback …	ELECTRON MICROSCOPY	3.43
8D9D	Human DNA polymerase-alpha/primase elongation complex II bound to primer/template	ELECTRON MICROSCOPY	3.59
5EXR	Crystal structure of human primosome	X-RAY DIFFRACTION	3.6
7OPL	CryoEM structure of DNA Polymerase alpha - primase bound to SARS CoV nsp1	ELECTRON MICROSCOPY	4.12
8D0K	Human CST-DNA polymerase alpha/primase preinitiation complex bound to 4xTEL-foldback …	ELECTRON MICROSCOPY	4.27
7U5C	Cryo-EM structure of human CST bound to DNA polymerase alpha-primase in a recruitment …	ELECTRON MICROSCOPY	4.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P49643-F1	81.11	0.49

Human Protein Atlas

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

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): nucleoplasm

Antibody reliability (HPA): IF supported

Functional residue map

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

Ligand- & substrate-binding residues (4)

Position	Role
287	[4Fe-4S] cluster
367	[4Fe-4S] cluster
384	[4Fe-4S] cluster
424	[4Fe-4S] cluster

Post-translational modifications (1)

Type	Positions
Phosphothreonine	470

Mutagenesis-validated functional residues (5)

Position	Phenotype
97	decreases primase affinity for pola1 by 10-fold.
104	decreases primase affinity for pola1 by 40-fold.
107	decreases primase affinity for pola1 by 30-fold.
108	decreases primase affinity for pola1 by 40-fold.
256–270	decreases rna primer di-nucleotide formation about 5-fold. does not affect the ratio between the di-nucleotide and its extension products.

Function

Pathways and Gene Ontology

Reactome pathways

9 curated (TAS) of 27; 3 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

27 pathways:

ID	Pathway	Evidence
R-HSA-9710421	Defective pyroptosis ⚕	curated
R-HSA-68962	Activation of the pre-replicative complex	curated
R-HSA-68952	DNA replication initiation	curated
R-HSA-113501	Inhibition of replication initiation of damaged DNA by RB1/E2F1	curated
R-HSA-69091	Polymerase switching	curated
R-HSA-174411	Polymerase switching on the C-strand of the telomere	curated
R-HSA-69183	Processive synthesis on the lagging strand	curated
R-HSA-69166	Removal of the Flap Intermediate	curated
R-HSA-174430	Telomere C-strand synthesis initiation	curated
R-HSA-1643685	Disease ⚕	—
R-HSA-9645723	Diseases of programmed cell death ⚕	—
R-HSA-1640170	Cell Cycle	—
R-HSA-69278	Cell Cycle, Mitotic	—
R-HSA-73886	Chromosome Maintenance	—
R-HSA-69306	DNA Replication	—
R-HSA-69002	DNA Replication Pre-Initiation	—
R-HSA-69190	DNA strand elongation	—
R-HSA-113510	E2F mediated regulation of DNA replication	—
R-HSA-180786	Extension of Telomeres	—
R-HSA-69206	G1/S Transition	—
R-HSA-69186	Lagging Strand Synthesis	—
R-HSA-69109	Leading Strand Synthesis	—
R-HSA-453279	Mitotic G1 phase and G1/S transition	—
R-HSA-69242	S Phase	—
R-HSA-69239	Synthesis of DNA	—
R-HSA-174417	Telomere C-strand (Lagging Strand) Synthesis	—
R-HSA-157579	Telomere Maintenance	—

MSigDB gene sets: 291 (showing top): REACTOME_INHIBITION_OF_REPLICATION_INITIATION_OF_DAMAGED_DNA_BY_RB1_E2F1, REACTOME_DNA_REPLICATION, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, WALLACE_PROSTATE_CANCER_RACE_UP, MORF_MSH3, PAL_PRMT5_TARGETS_UP, MORF_BRCA1, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, ACEVEDO_LIVER_CANCER_WITH_H3K27ME3_UP, MORF_RAD51L3, GOLDRATH_ANTIGEN_RESPONSE, PATIL_LIVER_CANCER, WEI_MYCN_TARGETS_WITH_E_BOX, GOCC_NUCLEAR_REPLICATION_FORK, LI_WILMS_TUMOR_VS_FETAL_KIDNEY_1_DN

GO Biological Process (3): DNA replication, synthesis of primer (GO:0006269), DNA replication initiation (GO:0006270), DNA replication (GO:0006260)

GO Molecular Function (7): DNA binding (GO:0003677), metal ion binding (GO:0046872), 4 iron, 4 sulfur cluster binding (GO:0051539), DNA/RNA hybrid binding (GO:0071667), DNA-directed RNA polymerase activity (GO:0003899), protein binding (GO:0005515), iron-sulfur cluster binding (GO:0051536)

GO Cellular Component (2): nucleoplasm (GO:0005654), alpha DNA polymerase:primase complex (GO:0005658)

Reactome top-level categories

15 top-level categories:

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

GO top-level categories

15 GO namespaces:

Category	Terms
DNA-templated DNA replication	2
RNA biosynthetic process	2
DNA metabolic process	2
nucleic acid binding	2
DNA biosynthetic process	1
cation binding	1
iron-sulfur cluster binding	1
5’-3’ RNA polymerase activity	1
binding	1
metal cluster binding	1
nuclear lumen	1
cellular anatomical structure	1
DNA polymerase complex	1
nuclear replisome	1
nuclear DNA-directed RNA polymerase complex	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 6 of 12 annotations. The rest are phylogenetic / computational / electronic (IEA).

6 experimentally-supported GO terms:

GO term	NS	Evidence
DNA replication initiation	BP	direct assay
DNA replication, synthesis of primer	BP	direct assay
alpha DNA polymerase:primase complex	CC	direct assay
nucleoplasm	CC	direct assay
4 iron, 4 sulfur cluster binding	MF	direct assay
DNA/RNA hybrid binding	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 1,566 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PRIM2	PRIM1	P49642	989
PRIM2	POLA2	Q14181	988
PRIM2	POLA1	P09884	770
PRIM2	POLE2	P56282	623
PRIM2	POLD1	P28340	601
PRIM2	POLD2	P49005	565
PRIM2	CDC45	O75419	561
PRIM2	RFC3	P40938	551
PRIM2	POLE	Q07864	535
PRIM2	RFC4	P35249	515
PRIM2	DNA2	P51530	514
PRIM2	YAE1	Q9NRH1	513
PRIM2	MCM7	P33993	506
PRIM2	WDHD1	O75717	506
PRIM2	MCM10	Q7L590	492

IntAct

Human interaction partners of PRIM2 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

9 partners by confidence:

Partner	Interaction type	MIscore	Records
PRIM1	physical association	0.740	6
RECK	physical association	0.560	3
SPRED1	physical association	0.560	3
PM20D2	association	0.530	1
RPA1	direct interaction	0.440	1
YWHAZ	physical association	0.400	1
E6	physical association	0.370	1
KDM1A	physical association	0.370	1
SUV39H1	physical association	0.370	1

BioGRID (159 interactions; top human partners by supporting records): PRIM1 (Affinity Capture-MS; 7 records), POLA1 (Reconstituted Complex; 6 records), MMS19 (Affinity Capture-MS; 5 records), POLA2 (Reconstituted Complex; 4 records), RAE1 (Affinity Capture-MS; 4 records), CIAO1 (Affinity Capture-Western; 3 records), KLHL20 (Affinity Capture-MS; 3 records), PRPS2 (Affinity Capture-MS; 3 records), DUSP9 (Affinity Capture-MS; 2 records), ERP44 (Affinity Capture-MS; 2 records), NLGN4Y (Affinity Capture-MS; 2 records), PARK2 (Affinity Capture-MS; 2 records), PM20D2 (Affinity Capture-MS; 2 records), RGS20 (Affinity Capture-MS; 2 records), RNF31 (Affinity Capture-MS; 2 records)

SIGNOR signaling

3 signaling interactions:

A	Effect	B	Mechanism
clofarabine	“down-regulates activity”	PRIM2	“chemical inhibition”
PRIM2	“form complex”	“DNA primase complex”	binding
“iron-sulfur cluster”	“up-regulates activity”	PRIM2	“chemical activation”

Protein complexes (CORUM) (5)

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

5 complexes by size:

Complex	Subunits	Members
★ 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
★ 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 alpha-primase complex	4	POLA1, POLA2, PRIM1, PRIM2

Disease & clinical

Genetic variants

Variant evidence for PRIM2: 31 ClinVar records (0 pathogenic / likely pathogenic); 6 GWAS associations.

ClinVar

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

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

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 28 predictions of 2,329):

Position(s)	Effect	Δscore	Sites
6:57320455–57320456	acceptor_loss	1.0000	6
6:57320561–57320562	donor_loss	1.0000	4
6:57324183	acceptor_gain	1.0000
6:57324199	acceptor_gain	1.0000
6:57324199–57324200	acceptor_loss	1.0000	4
6:57325923–57325924	acceptor_loss	1.0000	4
6:57326046–57326047	donor_loss	1.0000	5
6:57379997	donor_loss	1.0000
6:57382025	acceptor_gain	1.0000
6:57382029	acceptor_loss	1.0000

AlphaMissense

1,407 missense substitutions predicted likely pathogenic (of 3,381 scored), across 323 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
M288	9	0.941	0.993
H103	8	0.992	0.999
D99	8	0.988	0.997
H300	8	0.988	1.000
H443	8	0.985	0.997
H351	8	0.983	1.000
H382	8	0.983	0.996
F341	8	0.974	0.999
F42	8	0.973	0.997
F312	8	0.954	0.999
F331	8	0.954	0.997
F386	8	0.951	0.999
D380	8	0.948	0.996
H303	8	0.943	0.999
S451	8	0.940	0.999
F120	8	0.936	0.999
F428	8	0.936	0.996
D243	8	0.931	0.979
D126	8	0.915	0.989
H299	8	0.914	0.991

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
Kidney Chromophobe (TCGA)	unfavorable	1.03e-07
Liver Hepatocellular Carcinoma (validation)	unfavorable	1.38e-05
Liver Hepatocellular Carcinoma (TCGA)	unfavorable	2.28e-05
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	0.000271
Ovary Serous Cystadenocarcinoma (TCGA)	favorable	0.000695
Lung Adenocarcinoma (validation)	unfavorable	0.000959

Disease associations

OMIM: gene MIM:176636 | disease phenotypes:

GWAS associations

6 associations:

Study	Trait	p-value
GCST010866_85	Coronary artery disease	2e-17
GCST007576_310	Chronotype	8e-13
GCST011494_106	Daytime nap	8e-13
GCST011365_82	Myocardial infarction	7e-8
GCST005752_153	Systemic lupus erythematosus	6e-7
GCST002444_3	Plasma omega-6 polyunsaturated fatty acid levels (dihomo-gamma-linolenic acid)	4e-6

EFO canonical traits (from GWAS)

3 canonical traits:

EFO ID	Trait name
EFO:0005680	omega-6 polyunsaturated fatty acid measurement
EFO:0008328	chronotype measurement
EFO:0007828	daytime rest measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2363042 (PROTEIN FAMILY)

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases expression, decreases expression	4
bisphenol A	decreases expression, decreases methylation, increases expression, affects cotreatment, increases methylation	3
manganese chloride	decreases expression, increases abundance, increases expression	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	2
Manganese	increases abundance, increases expression, decreases expression	2
Phenylmercuric Acetate	decreases expression, affects cotreatment	2
Tobacco Smoke Pollution	affects expression, increases expression	2
Valproic Acid	increases expression	2
Cyclosporine	decreases expression	2
bisphenol F	affects cotreatment, increases expression	1
TAK-243	increases sumoylation	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
2,2’-methylenebis(4-methyl-6-tert-butylphenol)	affects expression, affects response to substance	1
VX-agent	increases expression	1
trichostatin A	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	increases abundance, increases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
epigallocatechin gallate	decreases expression, affects cotreatment	1
2,3,5-(triglutathion-S-yl)hydroquinone	increases ADP-ribosylation	1
K 7174	decreases expression	1
ICG 001	increases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	affects cotreatment, increases expression	1
LDN 193189	affects cotreatment, decreases expression	1
NSC668394	increases expression	1
Dasatinib	decreases expression	1

Clinical trials (associated diseases)

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