POLM

Summary

POLM (DNA polymerase mu, HGNC:9185) is a protein-coding gene on chromosome 7p13, encoding DNA-directed DNA/RNA polymerase mu (Q9NP87). Catalyzes template-directed nucleotide addition during gap filling at DNA double-strand breaks.

Predicted to enable DNA-directed DNA polymerase activity. Predicted to be involved in double-strand break repair via nonhomologous end joining. Predicted to act upstream of or within B cell differentiation and somatic hypermutation of immunoglobulin genes. Located in nucleoplasm.

Source: NCBI Gene 27434 — automated summary from GO annotations (Alliance of Genome Resources).

At a glance

• Clinical variants (ClinVar): 91 total — 1 pathogenic
• GTEx eGene: eQTL in 49 tissues, sQTL in 33 (q < 0.05)
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.18 (unconstrained)
• MANE Select transcript: NM_013284
• Notable: 91 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9185
Approved symbol	POLM
Name	DNA polymerase mu
Location	7p13
Locus type	gene with protein product
Status	Approved
Aliases	Tdt-N
Ensembl gene	ENSG00000122678
Ensembl biotype	protein_coding
OMIM	606344
Entrez	27434

Gene structure

Transcript identifiers

Ensembl transcripts: 92 — 50 protein_coding, 35 nonsense_mediated_decay, 6 retained_intron, 1 protein_coding_CDS_not_defined

MANE Select: ENST00000242248

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 7, TSL 2: 6, TSL 3: 2, TSL 4: 2, TSL 5: 1

ENST00000242248, ENST00000335195, ENST00000395831, ENST00000414235, ENST00000418926, ENST00000430942, ENST00000434229, ENST00000435068, ENST00000445616, ENST00000452049, ENST00000458246, ENST00000467607, ENST00000483644, ENST00000492312, ENST00000492321, ENST00000492605, ENST00000492971, ENST00000497300, ENST00000881064, ENST00000881065, ENST00000881066, ENST00000881067, ENST00000881068, ENST00000881069, ENST00000881070, ENST00000881071, ENST00000881072, ENST00000881073, ENST00000881074, ENST00000881075, ENST00000881076, ENST00000881077, ENST00000881078, ENST00000881079, ENST00000935513, ENST00000935514, ENST00000935515, ENST00000935516, ENST00000965029, ENST00000965030, ENST00000965031, ENST00000965032, ENST00000965033, ENST00000965034, ENST00000965035, ENST00000965036, ENST00000965037, ENST00000965038, ENST00000965039, ENST00000965040, ENST00000965041, ENST00000982934, ENST00000982935, ENST00000982936, ENST00000982937, ENST00000982938, ENST00000982939, ENST00000982940, ENST00000982941, ENST00000982942, ENST00000982943, ENST00000982944, ENST00000982945, ENST00000982946, ENST00000982947, ENST00000982948, ENST00000982949, ENST00000982950, ENST00000982951, ENST00001038983, ENST00001038984, ENST00001038985, ENST00001038986, ENST00001038987, ENST00001038988, ENST00001038989, ENST00001038990, ENST00001038991, ENST00001038992, ENST00001038993, ENST00001038994, ENST00001038995, ENST00001038996, ENST00001038997, ENST00001038998, ENST00001038999, ENST00001039000, ENST00001090071, ENST00001090072, ENST00001090073, ENST00001090074, ENST00001090075

RefSeq mRNA: 4 — MANE Select: NM_013284 NM_001284330, NM_001284331, NM_001362683, NM_013284

CCDS: CCDS34625, CCDS64635, CCDS64636

Canonical transcript exons

ENST00000242248 — 11 exons

Exon	Start	End
ENSE00000832554	44078740	44078811
ENSE00001233387	44074131	44074233
ENSE00001646543	44082251	44082530
ENSE00003477356	44079861	44079959
ENSE00003478855	44073783	44074025
ENSE00003536880	44073625	44073708
ENSE00003561565	44074398	44074530
ENSE00003573332	44076509	44076629
ENSE00003596529	44080733	44080916
ENSE00003684288	44079571	44079741
ENSE00003845509	44072062	44073377

Expression profiles

Bgee: expression breadth ubiquitous, 140 present calls, max score 93.88.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 16.6747 / max 164.1732, expressed in 1806 samples.

Highest expression (Bgee): granulocyte, metanephros cortex, lobe of thyroid gland, spleen, thyroid gland.

Genetic regulation across tissues (GTEx eQTL / sQTL)

POLM is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 49 tissues and its splicing (sQTL) in 33 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 82 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Thyroid	eqtl	1.1e-83	+0.96	7:44070954:TAAA:T
Nerve Tibial	eqtl	1.2e-72	+1.10	7:44062097:G:A
Skin Not Sun Exposed Suprapubic	eqtl	3.1e-68	+0.84	7:44062097:G:A
Whole Blood	eqtl	2.7e-62	+0.65	7:44070954:TAAA:T
Skin Sun Exposed Lower leg	eqtl	6.0e-42	+0.67	7:44070954:TAAA:T
Esophagus Mucosa	eqtl	1.8e-41	+0.66	7:44062097:G:A
Adipose Visceral Omentum	eqtl	4.9e-38	+0.61	7:44062097:G:A
Adipose Subcutaneous	eqtl	4.1e-34	+0.75	7:44070954:TAAA:T
Pituitary	eqtl	1.1e-33	+1.05	7:44071590:T:C
Stomach	eqtl	1.1e-32	+0.65	7:44062097:G:A
Adrenal Gland	eqtl	2.6e-32	+0.73	7:44062097:G:A
Colon Transverse	eqtl	1.4e-31	+0.61	7:44070954:TAAA:T
Pancreas	eqtl	3.9e-31	+0.91	7:44070954:TAAA:T
Nerve Tibial	sqtl	4.9e-30	-1.32	7:44071590:T:C
Thyroid	sqtl	6.2e-30	+1.09	7:44070954:TAAA:T
Breast Mammary Tissue	eqtl	2.9e-29	+0.73	7:44062097:G:A
Lung	eqtl	8.5e-26	+0.74	7:44071590:T:C
Lung	sqtl	1.9e-25	-1.33	7:44071590:T:C
Testis	eqtl	8.2e-24	+0.49	7:44062097:G:A
Skin Sun Exposed Lower leg	sqtl	1.8e-23	-1.12	7:44070954:TAAA:T

FANTOM5 promoters

8 alternative TSS:

Promoter ID	TPM avg	Samples expressed
83840	14.9229	1803
83837	0.4773	248
83834	0.3641	119
83839	0.2897	142
83833	0.2868	99
83836	0.2022	97
83835	0.0902	29
83838	0.0414	8

Top tissues by expression

showing 100 of 143 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	93.88	gold quality
metanephros cortex	UBERON:0010533	92.05	gold quality
right lobe of thyroid gland	UBERON:0001119	92.04	gold quality
spleen	UBERON:0002106	91.81	gold quality
left lobe of thyroid gland	UBERON:0001120	91.75	gold quality
thyroid gland	UBERON:0002046	91.51	gold quality
blood	UBERON:0000178	91.20	gold quality
right uterine tube	UBERON:0001302	89.84	gold quality
right lobe of liver	UBERON:0001114	89.79	gold quality
lower esophagus mucosa	UBERON:0035834	89.78	gold quality
lymph node	UBERON:0000029	89.64	gold quality
cortex of kidney	UBERON:0001225	89.38	gold quality
fundus of stomach	UBERON:0001160	89.14	gold quality
mucosa of stomach	UBERON:0001199	89.01	gold quality
body of stomach	UBERON:0001161	88.95	gold quality
left ovary	UBERON:0002119	88.87	gold quality
prostate gland	UBERON:0002367	88.86	gold quality
small intestine Peyer’s patch	UBERON:0003454	88.68	gold quality
endocervix	UBERON:0000458	88.49	gold quality
vagina	UBERON:0000996	88.48	gold quality
ectocervix	UBERON:0012249	88.29	gold quality
tibial artery	UBERON:0007610	88.26	gold quality
popliteal artery	UBERON:0002250	88.24	gold quality
small intestine	UBERON:0002108	88.16	gold quality
esophagus mucosa	UBERON:0002469	88.12	gold quality
right ovary	UBERON:0002118	88.06	gold quality
ovary	UBERON:0000992	88.05	gold quality
minor salivary gland	UBERON:0001830	87.80	gold quality
right atrium auricular region	UBERON:0006631	87.75	gold quality
saliva-secreting gland	UBERON:0001044	87.58	gold quality
pituitary gland	UBERON:0000007	87.56	gold quality
ascending aorta	UBERON:0001496	87.55	gold quality
sural nerve	UBERON:0015488	87.43	gold quality
stomach	UBERON:0000945	87.41	gold quality
thoracic aorta	UBERON:0001515	87.34	gold quality
uterine cervix	UBERON:0000002	87.22	gold quality
apex of heart	UBERON:0002098	87.20	gold quality
right coronary artery	UBERON:0001625	87.05	gold quality
tibial nerve	UBERON:0001323	87.03	gold quality
duodenum	UBERON:0002114	86.93	gold quality
transverse colon	UBERON:0001157	86.90	gold quality
descending thoracic aorta	UBERON:0002345	86.90	gold quality
vermiform appendix	UBERON:0001154	86.89	gold quality
subcutaneous adipose tissue	UBERON:0002190	86.88	gold quality
left uterine tube	UBERON:0001303	86.85	gold quality
skin of leg	UBERON:0001511	86.81	gold quality
esophagus	UBERON:0001043	86.79	gold quality
body of uterus	UBERON:0009853	86.67	gold quality
body of pancreas	UBERON:0001150	86.64	gold quality
thoracic mammary gland	UBERON:0005200	86.62	gold quality
zone of skin	UBERON:0000014	86.60	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	86.59	gold quality
left coronary artery	UBERON:0001626	86.53	gold quality
skin of abdomen	UBERON:0001416	86.42	gold quality
adenohypophysis	UBERON:0002196	86.41	gold quality
right hemisphere of cerebellum	UBERON:0014890	86.40	gold quality
right lung	UBERON:0002167	86.38	gold quality
upper lobe of left lung	UBERON:0008952	86.18	gold quality
mucosa of transverse colon	UBERON:0004991	86.12	gold quality
right adrenal gland cortex	UBERON:0035827	85.98	gold quality
right adrenal gland	UBERON:0001233	85.93	gold quality
intestine	UBERON:0000160	85.86	gold quality
fallopian tube	UBERON:0003889	85.82	gold quality
lower esophagus	UBERON:0013473	85.74	gold quality
gall bladder	UBERON:0002110	85.72	gold quality
adipose tissue	UBERON:0001013	85.71	gold quality
lower esophagus muscularis layer	UBERON:0035833	85.71	gold quality
cerebellar hemisphere	UBERON:0002245	85.64	gold quality
colon	UBERON:0001155	85.61	gold quality
heart	UBERON:0000948	85.59	gold quality
cerebellar cortex	UBERON:0002129	85.58	gold quality
cerebellum	UBERON:0002037	85.53	gold quality
muscle layer of sigmoid colon	UBERON:0035805	85.45	gold quality
heart left ventricle	UBERON:0002084	85.31	gold quality
liver	UBERON:0002107	85.31	gold quality
tonsil	UBERON:0002372	85.31	gold quality
adult mammalian kidney	UBERON:0000082	85.30	gold quality
myometrium	UBERON:0001296	85.23	gold quality
left adrenal gland cortex	UBERON:0035825	85.22	gold quality
left adrenal gland	UBERON:0001234	85.05	gold quality
anatomical system	UBERON:0000467	84.98	gold quality
material anatomical entity	UBERON:0000465	84.95	gold quality
multicellular organism	UBERON:0000468	84.95	gold quality
omental fat pad	UBERON:0010414	84.48	gold quality
hindlimb stylopod muscle	UBERON:0004252	84.38	gold quality
skeletal muscle tissue	UBERON:0001134	84.20	gold quality
gastrocnemius	UBERON:0001388	84.20	gold quality
kidney	UBERON:0002113	84.19	gold quality
adrenal gland	UBERON:0002369	84.12	gold quality
urinary bladder	UBERON:0001255	84.09	gold quality
muscle of leg	UBERON:0001383	84.06	gold quality
muscle organ	UBERON:0001630	84.03	gold quality
lung	UBERON:0002048	84.03	gold quality
skeletal muscle organ	UBERON:0014892	84.03	gold quality
leukocyte	CL:0000738	83.76	gold quality
bone marrow cell	CL:0002092	83.74	gold quality
bone marrow	UBERON:0002371	83.60	gold quality
monocyte	CL:0000576	83.48	gold quality
muscle tissue	UBERON:0002385	83.31	gold quality
stromal cell of endometrium	CL:0002255	83.20	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.06

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 76 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM
Superior colliculi	tissue	15.8
Spinal cord	tissue	13.7
Substantia nigra	tissue	12.8
Medulla oblongata	tissue	11.4
Cerebellum	tissue	10.3
Hippocampal formation	tissue	10.3
Hypothalamus	tissue	10.2
Midbrain	tissue	9.8
Periaqueductal gray	tissue	9.8
Pons	tissue	9.7
Corpus callosum	tissue	9.7
Thymus	tissue	9.1
Thalamus	tissue	9.0
Cerebral cortex	tissue	8.6
Temporal cortex	tissue	8.6
Amygdala	tissue	8.5
Olfactory bulb	tissue	8.4
Septum	tissue	8.3
Entorhinal cortex	tissue	8.0
Ventral forebrain	tissue	7.9
Insular cortex	tissue	7.9
Motor cortex	tissue	7.7
Retrosplenial cortex	tissue	7.6
Prefrontal cortex	tissue	7.4
Retrosplenial and cingulate cortex	tissue	7.3
Putamen	tissue	7.2
Somatosensory cortex	tissue	7.2
Lymph node	tissue	7.1
Basal ganglia	tissue	7.0
Vagina	tissue	6.9
Spleen	tissue	6.9
Tonsil	tissue	6.7
Seminal vesicle	tissue	6.3
Occipital cortex	tissue	6.3
Ovary	tissue	6.0
Salivary gland	tissue	5.8
Pituitary gland	tissue	5.5
Skeletal muscle	tissue	5.5
Choroid plexus	tissue	5.5
Stomach 1	tissue	5.4
Pancreas	tissue	5.4
Duodenum	tissue	5.3
Fallopian tube	tissue	5.2
Heart muscle	tissue	5.1
Skin 1	tissue	5.0
Thyroid gland	tissue	4.7
Tongue	tissue	4.6
Locus coeruleus	tissue	4.4
Hippocampus	tissue	4.3
Gallbladder	tissue	4.2
Bone marrow	tissue	4.2
Appendix	tissue	4.2
Parathyroid gland	tissue	4.1
Retina	tissue	4.0
Cervix	tissue	3.9
Small intestine	tissue	3.7
Prostate	tissue	3.7
Adipose tissue	tissue	3.5
Endometrium 1	tissue	3.5
Epididymis	tissue	3.5

Brain sub-regions (HPA Brain Atlas): detected in 189; highest nTPM — Dorsal spinal cord (13.7), Ventral spinal cord (12.7), Ventral hippocampus (10.3), White matter (9.7), Subiculum (9.1).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HIF1A

miRNA regulators (miRDB)

Targeting POLM 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-4283	100.00	66.42	2097
HSA-MIR-518D-5P	100.00	67.51	979
HSA-MIR-518E-5P	100.00	67.66	954
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-519A-5P	100.00	67.66	954
HSA-MIR-519B-5P	100.00	67.66	954
HSA-MIR-519C-5P	100.00	67.66	954
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-4650-5P	99.98	64.69	999
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-6857-5P	99.87	65.32	985
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-659-3P	99.85	70.69	1620
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-1323	99.83	69.89	2471
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-548O-3P	99.74	69.30	2228
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-182-3P	99.57	67.57	825

Functional genomics

gnomAD constraint: pLI 9.16e-18, LOEUF 1.18, missense Z -0.532 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000242248 — one region, missense o/e 0.99.

Literature-anchored findings (GeneRIF, showing 28)

• DNA polymerase mu performs DNA synthesis at a AAF lesion (PMID:11972346)
• role in DNA repair (PMID:11974916)
• Association of DNA polymerase mu (pol mu) with Ku and ligase IV: role for pol mu in end-joining double-strand break repair. (PMID:12077346)
• DNA polymerase mu acts in response to several types of DNA damage with a lesion bypass mechanism (PMID:12228225)
• expression in B-cell non-Hodgkin’s lymphomas (PMID:12368208)
• Pol mu’s substrate specificity is similar to that of pol beta in most respects but has an approximately 1,000-fold-reduced ability to discriminate against ribonucleotides compared to pol beta (PMID:12640116)
• human DNA polymerase mu has a template-dependent, sequence-independent nucleotidyl transferase activity (PMID:14581466)
• Poliota incorporates a C opposite the gamma-HOPdG adduct with nearly the same efficiency as opposite a nonadducted G residue. The subsequent extension step is performed by Polkappa, which efficiently extends from the C incorporated opposite the adduct. (PMID:15199127)
• DNA polymerase mu has been overexpressed, purified, and its fidelity estimated for incorporation of both deoxynucleotides and ribonucleotides based on pre-steady-state kinetic data under single-turnover conditions. (PMID:15504045)
• Overexpression of DNA polymerase mu in a Burkitt’s lymphoma cell line induced an increase in somatic mutations specifically targeted to G/C residues in immunoglobulin variable genes. (PMID:15520469)
• Pol mu promotes accuracy during Ig kappa recombination. (PMID:16061182)
• When the terminal deoxynucleotidyl transferase (TdT) loop1 was deleted, human Polmu lacked TdT activity but improved DNA-binding and DNA template-dependent polymerization. (PMID:16963491)
• Studies shed light on the mechanism by which a rate-limited terminal transferase activity in Polmu could regulate the balance between accuracy and necessary efficiency, providing some variability during NHEJ. (PMID:19805281)
• Pol mu binds to DNA through its amino-terminal and pol beta-like regions. (PMID:22897684)
• The results uncovered a new DNA-binding function for the BRCT domain of Polmicro and demonstrated the importance of several residues located at the primer-binding region, for both DNA-binding and polymerization activities. (PMID:23034807)
• The study points at human Polmicro residues His(329) and Arg(387) as responsible for regulating nucleotide expansions occurring during DNA repair transactions, either promoting or blocking, respectively, iterative polymerization. (PMID:23143108)
• A physiological concentration of Mn(2+) ions did benefit Polmicro-mediated non-homologous end joining by improving the efficiency and accuracy of nucleotide insertion. (PMID:23275568)
• evidence suggests that Polmu could be regulated in vivo by phosphorylation of the BRCT domain (Ser12/Thr21) and of Ser372, affecting the function of loop1; Polmu’s most distinctive activities would be turned off at specific cell-cycle phases (S and G2), when these functions might be harmful to the cell (PMID:23933132)
• A specific N-terminal extension of the 8 kDa domain of DNA polymerase mu is potentially implicated in the maintenance of a closed conformation throughout the catalytic cycle, and this study indicated that it could be a target of Cdk phosphorylation. (PMID:23935073)
• specific loop 1 residues contribute to Pol mu’s unique ability to catalyze template-dependent NHEJ of DSBs with unpaired 3’ ends (PMID:24487959)
• A study of how Polmu fixes and/or orients the mobile Loop1 part of the protein in accordance with the substrate on which it is polymerizing. (PMID:24878922)
• analysis of template-dependent synthesis by human polymerase mu (PMID:26240373)
• Structural accommodation of ribonucleotide incorporation by the DNA repair enzyme polymerase Mu has been described. (PMID:28911097)
• Polmu point mutations affecting 2 conserved adjacent residues located in the 8 kDa domain, G174S and R175H, limit the efficiency of accurate NHEJ by Polmu in vitro and in vivo due to decreased template dependency during NHEJ, which renders the error-rate of the mutants higher due to the ability of Polmu to randomly incorporate nucleotides at DSBs. (PMID:28973441)
• pol mu-mediated deoxyguanosine triphosphate mismatch insertion opposite template base T coupled with ligation could be a feature of mutation prone nonhomologous end joining during double-strand break repair. (PMID:30310068)
• DNA polymerase mu: An inflexible scaffold for substrate flexibility. (PMID:33087269)
• DNA Polymerase and dRP-lyase activities of polymorphic variants of human Pol iota. (PMID:33600564)
• Mechanism of genome instability mediated by human DNA polymerase mu misincorporation. (PMID:34145298)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	polm	ENSDARG00000103470
mus_musculus	Polm	ENSMUSG00000020474
rattus_norvegicus	Polm	ENSRNOG00000013647

Paralogs (3): POLB (ENSG00000070501), DNTT (ENSG00000107447), POLL (ENSG00000166169)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1860191) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 7 distinct phenotype terms.

Mouse phenotype (MP)	Records
decreased B cell number	4
abnormal Peyer’s patch morphology	1
lymphoid hypoplasia	1
abnormal B cell number	1
abnormal lymphocyte morphology	1
abnormal B cell proliferation	1
abnormal immunoglobulin light chain V-J recombination	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
Macaca fascicularis	Q4R380	96.9%	Diamond
Eulemur macaco	A4PCD4	87.1%	Diamond
Bos taurus	P06526	87.1%	Diamond
Monodelphis domestica	O02789	69.9%	Diamond
Gallus gallus	P36195	65.1%	Diamond
Ambystoma mexicanum	O57486	58.7%	Diamond
Xenopus laevis	P42118	58.6%	Diamond
Oncorhynchus mykiss	Q92089	50.1%	Diamond

Genomic neighbors (locus context)

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

Symbol	Type	Entrez
MIR6838	ncRNA	102465504
AEBP1	protein-coding	165
DBNL	protein-coding	28988
PGAM2	protein-coding	5224
POLD2	protein-coding	5425
MIR4649	ncRNA	100616346
MIR6837	ncRNA	102466985
LINC00957	ncRNA	255031
SPDYE1	protein-coding	285955
MYL7	protein-coding	58498

Protein

Protein identifiers

DNA-directed DNA/RNA polymerase mu — Q9NP87 (reviewed: Q9NP87)

Alternative names: Terminal transferase

All UniProt accessions (9): A1PQG8, C9J222, C9JF34, Q9NP87, F8WB78, F8WDE4, F8WEJ1, H7C2M2, Q6PIY2

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes template-directed nucleotide addition during gap filling at DNA double-strand breaks. Functions as a gap-filling polymerase involved in repair of DNA double-strand breaks by non-homologous end joining (NHEJ). Displays reduced sugar discrimination, incorporating deoxyribonucleotides and ribonucleotides with similar efficiency on DNA primer strands, and is able to polymerize nucleotides on RNA-terminated primer strands in vitro. Participates in immunoglobulin (Ig) light chain gene rearrangement in V(D)J recombination.

Subcellular location. Nucleus.

Tissue specificity. Predominantly expressed in peripheral lymphoid tissues.

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

Isoforms (3)

UniProt ID	Names	Canonical?
Q9NP87-1	1	yes
Q9NP87-2	2
Q9NP87-3	3

RefSeq proteins (4): NP_001271259, NP_001271260, NP_001349612, NP_037416* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001357	BRCT_dom	Domain
IPR001726	TdT/Mu	Family
IPR002054	DNA-dir_DNA_pol_X	Domain
IPR010996	HHH_MUS81	Domain
IPR018944	DNA_pol_lambd_fingers_domain	Domain
IPR019843	DNA_pol-X_BS	Binding_site
IPR022312	DNA_pol_X	Family
IPR027249	DNA/RNApol_mu	Family
IPR027421	DNA_pol_lamdba_lyase_dom_sf	Homologous_superfamily
IPR028207	DNA_pol_B_palm_palm	Domain
IPR029398	PolB_thumb	Domain
IPR036420	BRCT_dom_sf	Homologous_superfamily
IPR037160	DNA_Pol_thumb_sf	Homologous_superfamily
IPR043519	NT_sf	Homologous_superfamily

Pfam: PF10391, PF14716, PF14791, PF14792

Enzyme classification (BRENDA)

• EC 2.7.7.7 — DNA-directed DNA polymerase (BRENDA: 139 organisms, 372 substrates, 325 inhibitors, 281 Km, 239 kcat entries)

Substrate kinetics (BRENDA)

52 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
DATP	0.0003–3.2	52
DCTP	0.0001–2.5	46
DTTP	0.0003–47.4	46
DGTP	0.0002–2.5	29
DEOXYNUCLEOSIDE TRIPHOSPHATE	0.0012–0.64	12
DNAN	—	7
7-DEAZA-2’-DEOXYADENOSINE 5’-TRIPHOSPHATE	0.0011–0.344	5
N1-METHYL-2’-DEOXYADENOSINE 5’-TRIPHOSPHATE	0.223–0.403	5
2-AMINOPURINE-2’-DEOXY-D-RIBOSE 5’-TRIPHOSPHATE	0.006–0.0144	2
2-THIO-DCTP	0.067–0.98	2
5-METHYL-DCTP	0.013–1.22	2
DAMP:DG	1.153–1.42	2
DCMP:DG	—	2
DGMP:DG	0.263–0.3511	2
DTMP:DG	1.26–1.43	2

Catalyzed reactions (Rhea)

• DNA(n) + a 2’-deoxyribonucleoside 5’-triphosphate = DNA(n+1) + diphosphate (RHEA:22508)
• DNA(n) + dCTP = DNA(n)-C + diphosphate (RHEA:86319)

UniProt features (62 total): helix 28, strand 13, splice variant 4, sequence variant 4, turn 4, binding site 3, region of interest 2, chain 1, domain 1, site 1, modified residue 1

Structure

Experimental structures (PDB)

showing 30 of 129 structures by resolution:

PDB	Title	Method	Resolution (Å)
7KTN	DNA Polymerase Mu, 8-oxodGTP:At Product State Ternary Complex, 10 mM Mg2+ (2160min)	X-RAY DIFFRACTION	1.33
7KT0	DNA Polymerase Mu, dGTP:At Ground State Ternary Complex, 50 mM Mg2+ (60min)	X-RAY DIFFRACTION	1.36
7KSZ	DNA Polymerase Mu, dGTP:At Pre-Catalytic Ground State Ternary Complex, 10 mM Ca2+ (960min)	X-RAY DIFFRACTION	1.42
7KTK	DNA Polymerase Mu (K438D), 8-oxodGTP:Ct Ground State Ternary Complex, 50 mM Mg2+ (90min)	X-RAY DIFFRACTION	1.42
7KTL	DNA Polymerase Mu (K438D), 8-oxodGTP:Ct Product State Ternary Complex, 50 mM Mn2+ (90min)	X-RAY DIFFRACTION	1.42
7KTG	DNA Polymerase Mu, 8-oxodGTP:Ct Product State Ternary Complex, 50 mM Mg2+ (960min)	X-RAY DIFFRACTION	1.45
7KTJ	DNA Polymerase Mu (K438D), 8-oxodGTP:Ct Pre-Catalytic Ground State Ternary Complex, 20 mM …	X-RAY DIFFRACTION	1.45
7KT5	DNA Polymerase Mu, 8-oxodGTP:At Product State Ternary Complex, 10 mM Mn2+ (120min)	X-RAY DIFFRACTION	1.46
7KTH	DNA Polymerase Mu, 8-oxodGTP:Ct Product State Ternary Complex, 10 mM Mg2+ (2160min)	X-RAY DIFFRACTION	1.48
7KTE	DNA Polymerase Mu, 8-oxodGTP:Ct Reaction State Ternary Complex, 50 mM Mg2+ (90min)	X-RAY DIFFRACTION	1.48
7KT9	DNA Polymerase Mu, 8-oxodGTP:At Product State Ternary Complex, 50 mM Mg2+ (960min)	X-RAY DIFFRACTION	1.48
7KTF	DNA Polymerase Mu, 8-oxodGTP:Ct Product State Ternary Complex, 50 mM Mg2+ (180min)	X-RAY DIFFRACTION	1.49
7KSW	DNA Polymerase Mu, dGTP:Ct Reaction State Ternary Complex, 10 mM Mg2+ (10min)	X-RAY DIFFRACTION	1.49
7KT2	DNA Polymerase Mu, dGTP:At Product State Ternary Complex, 50 mM Mn2+ (225min)	X-RAY DIFFRACTION	1.5
5VZB	Post-catalytic complex of human Polymerase Mu (G433S) mutant with incoming UTP	X-RAY DIFFRACTION	1.5
5VZI	Post-catalytic complex of human Polymerase Mu (W434H) mutant with incoming dTTP	X-RAY DIFFRACTION	1.5
6WID	Nucleotide incorporation intermediate into quaternary complex of human Polymerase Mu on a …	X-RAY DIFFRACTION	1.5
6WIE	Post-catalytic nicked complex of human Polymerase Mu on a complementary DNA double-strand …	X-RAY DIFFRACTION	1.5
5VZA	Pre-catalytic ternary complex of human Polymerase Mu (G433S) mutant with incoming …	X-RAY DIFFRACTION	1.5
7KSS	DNA Polymerase Mu, dGTP:Ct Pre-Catalytic Ground State Ternary Complex, 10 mM Ca2+ (20min)	X-RAY DIFFRACTION	1.5
5VZE	Post-catalytic complex of human Polymerase Mu (W434A) mutant with incoming UTP	X-RAY DIFFRACTION	1.51
6VF3	DNA Polymerase Mu, 8-oxorGTP:At Ground State Ternary Complex, 50 mM Mn2+ (15 min)	X-RAY DIFFRACTION	1.52
7KTM	DNA Polymerase Mu (K438D), 8-oxodGTP:Ct Reaction State Ternary Complex, 50 mM Mn2+ (30min)	X-RAY DIFFRACTION	1.53
6VFB	DNA Polymerase Mu, 8-oxorGTP:Ct Reaction State Ternary Complex, 50 mM Mn2+ (960 min)	X-RAY DIFFRACTION	1.55
6WIC	Pre-catalytic quaternary complex of human Polymerase Mu on a complementary DNA …	X-RAY DIFFRACTION	1.55
5VZ7	Pre-catalytic ternary complex of human Polymerase Mu (G433A) mutant with incoming …	X-RAY DIFFRACTION	1.55
7KTD	DNA Polymerase Mu, 8-oxodGTP:Ct Product State Ternary Complex, 10 mM Mn2+ (960min)	X-RAY DIFFRACTION	1.55
5VZC	Post-catalytic complex of human Polymerase Mu (G433S) mutant with incoming dTTP	X-RAY DIFFRACTION	1.55
6VF9	DNA Polymerase Mu, 8-oxorGTP:Ct Ternary Complex, 50 mM Mg2+ (2160 min)	X-RAY DIFFRACTION	1.56
7KSX	DNA Polymerase Mu, dGTP:Ct Product State Ternary Complex, 10 mM Mg2+ (30min)	X-RAY DIFFRACTION	1.57

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NP87-F1	89.39	0.78

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 supported

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)

Position	Role
433	responsible for the low discrimination between dntp and rntp

Ligand- & substrate-binding residues (3)

Position	Role
330	Mg(2+)
332	Mg(2+)
418	Mg(2+)

Post-translational modifications (1)

Type	Positions
Phosphoserine	12

Function

Pathways and Gene Ontology

Reactome pathways

1 curated (TAS) of 3; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

3 pathways:

ID	Pathway	Evidence
R-HSA-5693571	Nonhomologous End-Joining (NHEJ)	curated
R-HSA-5693532	DNA Double-Strand Break Repair	—
R-HSA-73894	DNA Repair	—

MSigDB gene sets: 132 (showing top): BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOBP_B_CELL_ACTIVATION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, KAUFFMANN_DNA_REPAIR_GENES, GOMF_DNA_POLYMERASE_ACTIVITY, GOBP_IMMUNOGLOBULIN_PRODUCTION, GOBP_DNA_DAMAGE_RESPONSE, GOBP_SOMATIC_DIVERSIFICATION_OF_IMMUNE_RECEPTORS, GOBP_DNA_BIOSYNTHETIC_PROCESS, WINTER_HYPOXIA_METAGENE, chr7p13, GOBP_SOMATIC_DIVERSIFICATION_OF_IMMUNE_RECEPTORS_VIA_SOMATIC_MUTATION, REACTOME_DNA_REPAIR, OCT1_B, NAKAMURA_METASTASIS_MODEL_DN

GO Biological Process (6): double-strand break repair via nonhomologous end joining (GO:0006303), DNA recombination (GO:0006310), DNA metabolic process (GO:0006259), DNA repair (GO:0006281), DNA damage response (GO:0006974), DNA biosynthetic process (GO:0071897)

GO Molecular Function (7): DNA binding (GO:0003677), DNA-directed DNA polymerase activity (GO:0003887), metal ion binding (GO:0046872), 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

2 top-level categories:

Category	Pathways
DNA Double-Strand Break Repair	1
DNA Repair	1

GO top-level categories

18 GO namespaces:

Category	Terms
DNA metabolic process	3
double-strand break repair	1
nucleic acid metabolic process	1
DNA damage response	1
cellular response to stress	1
nucleic acid biosynthetic process	1
nucleic acid binding	1
DNA polymerase activity	1
cation binding	1
binding	1
catalytic activity	1
transferase activity, transferring phosphorus-containing groups	1
nucleotidyltransferase activity	1
DNA biosynthetic process	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) — 1 of 15 annotations. The rest are phylogenetic / computational / electronic (IEA).

1 experimentally-supported GO terms:

GO term	NS	Evidence
nucleoplasm	CC	direct assay

Protein interactions and networks

STRING

showing 15 of 922 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
POLM	REV1	Q9UBZ9	952
POLM	TENT4A	Q5XG87	933
POLM	POLH	Q9Y253	906
POLM	POLI	Q9UNA4	855
POLM	PCNA	P12004	827
POLM	RAD18	Q9NS91	823
POLM	LIG1	P18858	800
POLM	REV3L	O60673	784
POLM	UNG	P13051	777
POLM	XRCC4	Q13426	737
POLM	MAD2L2	Q9UI95	716
POLM	NHEJ1	Q9H9Q4	715
POLM	POLB	P06746	700
POLM	XRCC6	P12956	673
POLM	PRIMPOL	Q96LW4	665

IntAct

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

4 partners by confidence:

Partner	Interaction type	MIscore	Records
MTUS1	physical association	0.400	1
CEP55	physical association	0.370	1
E7	physical association	0.370	1
CTU2	association	0.350	1

BioGRID (36 interactions; top human partners by supporting records): ACAD8 (Affinity Capture-MS; 2 records), CEP55 (Two-hybrid; 2 records), CTU2 (Affinity Capture-MS; 2 records), CTAG1A (Two-hybrid), CTAG1B (Two-hybrid), DDX58 (Affinity Capture-RNA), EEA1 (Cross-Linking-MS (XL-MS)), EFNA4 (Affinity Capture-MS), IKZF3 (Two-hybrid), KRAS (Synthetic Lethality), MTUS1 (Affinity Capture-MS), NUDT21 (Affinity Capture-RNA), OGT (Reconstituted Complex), PARP1 (Proximity Label-MS), PARP2 (Proximity Label-MS)

SIGNOR signaling

showing 1 of 3 signaling interactions:

A	Effect	B	Mechanism
CyclinA2/CDK2	“down-regulates activity”	POLM	phosphorylation

Disease & clinical

Genetic variants

Variant evidence for POLM: 91 ClinVar records (1 pathogenic / likely pathogenic). Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	68
Likely benign	8
Benign	1

Top pathogenic / likely-pathogenic (1)

Showing all 1 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
442833	GRCh37/hg19 7p22.3-q36.3(chr7:43361-159119707)	Pathogenic	no assertion criteria provided	1

Per-variant reference — Sugi Variant

Explore POLM’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 32 predictions of 1,287):

Position(s)	Effect	Δscore	Sites
7:44073709–44073710	acceptor_loss	1.0000	5
7:44074396–44074397	donor_loss	1.0000	3
7:44076507–44076508	donor_loss	1.0000	3
7:44080731–44080732	donor_loss	1.0000	4
7:44080930	acceptor_gain	1.0000
7:44082249–44082250	donor_loss	1.0000	3
7:44073623–44073624	donor_loss	0.9900	6
7:44073710	acceptor_loss	0.9900
7:44073711	acceptor_gain	0.9900
7:44073781–44073782	donor_loss	0.9900	5

AlphaMissense

546 missense substitutions predicted likely pathogenic (of 3,178 scored), across 185 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
F56	8	0.882	0.987
F479	8	0.865	0.947
D332	8	0.856	0.954
D418	8	0.812	0.908
D330	8	0.811	0.920
W104	7	0.935	0.979
F440	7	0.911	0.957
F321	7	0.876	0.971
W434	7	0.874	0.941
F46	7	0.867	0.969
F244	7	0.855	0.967
W254	7	0.831	0.954
F27	7	0.828	0.954
F240	7	0.812	0.927
F179	7	0.780	0.932
C143	7	0.778	0.921
E475	7	0.770	0.914
R492	6	0.887	0.977
R323	6	0.842	0.943
M39	6	0.799	0.857

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

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

2 prognostic cancer types:

Cancer	Prognostic	p-value
Lung Adenocarcinoma (TCGA)	unfavorable	0.000308
Pancreatic Adenocarcinoma (validation)	unfavorable	0.000663

Disease associations

OMIM: gene MIM:606344 | disease phenotypes:

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1914260 (SINGLE PROTEIN)

PharmGKB: 1 entry (CPIC guideline: no)

ChEMBL bioactivities

1 potent at pChembl≥5 of 2 total, top 1 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.10	IC50	7900	nM	CHEMBL1917196

PubChem BioAssay actives

1 with measured affinity, of 11 total; 1 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
(5,8-dioxonaphthalen-1-yl) dodecanoate	627960: Inhibition of His-tagged human DNA polymerase mu using poly(dA)/oligo(dT)18 (A/T = 2/1) and dTTP as the DNA template-primer and nucleotide substrate after 60 mins	ic50	7.9000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression, increases abundance	2
Estradiol	affects cotreatment, increases expression, affects expression	2
triphenyl phosphate	affects expression	1
alpha-pinene	increases abundance, affects cotreatment, decreases expression	1
bisphenol A	increases expression	1
beta-lapachone	increases expression	1
coumarin	increases phosphorylation	1
methacrylaldehyde	increases abundance, affects cotreatment, decreases expression	1
beta-methylcholine	affects expression	1
MK-886	decreases activity	1
di-n-butylphosphoric acid	affects expression	1
abrine	increases expression	1
Bortezomib	decreases expression	1
Acrolein	affects cotreatment, decreases expression, increases abundance	1
Air Pollutants	affects cotreatment, decreases expression, increases abundance	1
Amphotericin B	increases expression	1
Arsenic	increases abundance, increases expression	1
Benzo(a)pyrene	decreases methylation	1
Caffeine	increases phosphorylation	1
Cisplatin	increases expression	1
Cyclophosphamide	increases expression	1
Doxorubicin	decreases expression	1
Gentamicins	increases expression	1
Ozone	affects cotreatment, decreases expression, increases abundance	1
Smoke	decreases expression	1
Taurine	increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Okadaic Acid	decreases expression	1
Raloxifene Hydrochloride	increases expression	1
Volatile Organic Compounds	affects cotreatment, decreases expression	1

ChEMBL screening assays

5 unique, capped per target: 5 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1919787	Binding	Inhibition of His-tagged human DNA polymerase mu using poly(dA)/oligo(dT)18 (A/T = 2/1) and dTTP as the DNA template-primer and nucleotide substrate after 60 mins	Inhibitory effect of novel 5-O-acyl juglones on mammalian DNA polymerase activity, cancer cell growth and inflammatory response. — *Bioorg Med Chem*

Cellosaurus cell lines

5 cell lines: 5 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_1R07	HCT116-POLM(+/-)	Cancer cell line	Male
CVCL_B2BH	Abcam HeLa POLM KO	Cancer cell line	Female
CVCL_TF06	HAP1 POLM (-) 1	Cancer cell line	Male
CVCL_TF07	HAP1 POLM (-) 2	Cancer cell line	Male
CVCL_TF08	HAP1 POLM (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

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

Predicted chemistry — Sugi Predict

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