NSMCE4A

Summary

NSMCE4A (NSE4A component of SMC5/6 complex, HGNC:25935) is a protein-coding gene on chromosome 10q26.13, encoding Non-structural maintenance of chromosomes element 4 homolog A (Q9NXX6). Component of the SMC5-SMC6 complex, a complex involved in DNA double-strand breaks by homologous recombination. It is a selective cancer dependency (DepMap: 29.9% of cell lines).

Involved in DNA damage response. Located in nuclear body. Part of Smc5-Smc6 complex.

Source: NCBI Gene 54780 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 64 total
• Cancer dependency (DepMap): dependent in 29.9% of screened cell lines
• MANE Select transcript: NM_017615

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25935
Approved symbol	NSMCE4A
Name	NSE4A component of SMC5/6 complex
Location	10q26.13
Locus type	gene with protein product
Status	Approved
Aliases	FLJ20003, bA500G22.3, NSE4A
Ensembl gene	ENSG00000107672
Ensembl biotype	protein_coding
OMIM	612987
Entrez	54780

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 14 protein_coding, 6 protein_coding_CDS_not_defined, 3 retained_intron

ENST00000369017, ENST00000369023, ENST00000459911, ENST00000464321, ENST00000465189, ENST00000468209, ENST00000472431, ENST00000477289, ENST00000481320, ENST00000483541, ENST00000489266, ENST00000869011, ENST00000869012, ENST00000869013, ENST00000869014, ENST00000869015, ENST00000869016, ENST00000869017, ENST00000869018, ENST00000931741, ENST00000950576, ENST00000950577, ENST00000950578

RefSeq mRNA: 3 — MANE Select: NM_017615 NM_001167865, NM_001411073, NM_017615

CCDS: CCDS7624, CCDS91366

Canonical transcript exons

ENST00000369023 — 11 exons

Exon	Start	End
ENSE00001844635	121957091	121957259
ENSE00001873714	121974874	121975217
ENSE00003483767	121967655	121967806
ENSE00003495026	121959324	121959410
ENSE00003502168	121963238	121963328
ENSE00003513615	121965286	121965385
ENSE00003540247	121960358	121960406
ENSE00003544726	121970939	121971069
ENSE00003578078	121974004	121974081
ENSE00003602728	121959501	121959595
ENSE00003675958	121961423	121961517

Expression profiles

Bgee: expression breadth ubiquitous, 282 present calls, max score 99.47.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 27.4901 / max 263.5127, expressed in 1811 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
111753	25.0282	1811
111754	1.5886	965
111752	0.8734	555

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
oocyte	CL:0000023	99.47	gold quality
secondary oocyte	CL:0000655	98.74	gold quality
mucosa of stomach	UBERON:0001199	98.13	gold quality
parotid gland	UBERON:0001831	97.88	gold quality
body of pancreas	UBERON:0001150	97.62	gold quality
muscle layer of sigmoid colon	UBERON:0035805	97.61	gold quality
lower esophagus muscularis layer	UBERON:0035833	97.42	gold quality
lower esophagus	UBERON:0013473	97.41	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	97.34	gold quality
small intestine Peyer’s patch	UBERON:0003454	97.24	gold quality
minor salivary gland	UBERON:0001830	97.13	gold quality
saliva-secreting gland	UBERON:0001044	97.09	gold quality
rectum	UBERON:0001052	97.00	gold quality
transverse colon	UBERON:0001157	96.85	gold quality
body of uterus	UBERON:0009853	96.84	gold quality
body of stomach	UBERON:0001161	96.83	gold quality
skin of abdomen	UBERON:0001416	96.80	gold quality
left ovary	UBERON:0002119	96.80	gold quality
right lung	UBERON:0002167	96.79	gold quality
right ovary	UBERON:0002118	96.73	gold quality
right uterine tube	UBERON:0001302	96.71	gold quality
ectocervix	UBERON:0012249	96.69	gold quality
left lobe of thyroid gland	UBERON:0001120	96.66	gold quality
skin of leg	UBERON:0001511	96.65	gold quality
endocervix	UBERON:0000458	96.64	gold quality
calcaneal tendon	UBERON:0003701	96.59	gold quality
tibial nerve	UBERON:0001323	96.54	gold quality
right lobe of thyroid gland	UBERON:0001119	96.53	gold quality
prostate gland	UBERON:0002367	96.35	gold quality
spleen	UBERON:0002106	96.33	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-7303	no	241.68
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

13 targeting NSMCE4A, 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-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-221-3P	99.86	71.56	1329
HSA-MIR-222-3P	99.86	71.35	1337
HSA-MIR-154-3P	99.50	70.05	831
HSA-MIR-487A-3P	99.50	69.95	840
HSA-MIR-409-3P	99.50	66.33	1192
HSA-MIR-5001-3P	98.91	67.28	1394
HSA-MIR-6837-3P	98.42	66.71	1149
HSA-MIR-15B-3P	97.85	66.68	974
HSA-MIR-5009-5P	94.82	63.89	775
HSA-MIR-8074	90.61	65.46	165

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 29.9% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 1)

• TRIM31 directly binds to NSE4, suggesting the existence of a TRIM31-MAGEA1-NSE4 complex reminiscent of the NSE1-NSE3-NSE4 trimer. (PMID:25590999)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Nsmce4a	ENSMUSG00000040331
rattus_norvegicus	Nsmce4a	ENSRNOG00000020452

Paralogs (1): EID3 (ENSG00000255150)

Protein

Protein identifiers

Non-structural maintenance of chromosomes element 4 homolog A — Q9NXX6 (reviewed: Q9NXX6)

All UniProt accessions (1): Q9NXX6

UniProt curated annotations — full annotation on UniProt →

Function. Component of the SMC5-SMC6 complex, a complex involved in DNA double-strand breaks by homologous recombination. The complex may promote sister chromatid homologous recombination by recruiting the SMC1-SMC3 cohesin complex to double-strand breaks. The complex is required for telomere maintenance via recombination in ALT (alternative lengthening of telomeres) cell lines and mediates sumoylation of shelterin complex (telosome) components which is proposed to lead to shelterin complex disassembly in ALT-associated PML bodies (APBs). Is involved in positive regulation of response to DNA damage stimulus.

Subunit / interactions. Component of the SMC5-SMC6 complex which consists at least of SMC5, SMC6, NSMCE2, NSMCE1, NSMCE4A or EID3 and NSMCE3. NSMCE1, NSMCE4A or EID3 and NSMCE3 probably form a subcomplex that bridges the head domains of the SMC5:SMC6 heterodimer. Interacts with NSMCE3.

Subcellular location. Nucleus. Chromosome. Telomere.

Similarity. Belongs to the NSE4 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9NXX6-1	1	yes
Q9NXX6-2	2

RefSeq proteins (3): NP_001161337, NP_001398002, NP_060085* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR014854	Nse4_C	Domain
IPR027786	Nse4/EID	Family
IPR029225	Nse4_Nse3-bd	Domain

Pfam: PF08743, PF15412

UniProt features (12 total): compositionally biased region 3, sequence conflict 2, modified residue 2, splice variant 2, chain 1, region of interest 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NXX6-F1	70.30	0.25

Functional residue map

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

Post-translational modifications (2): 345, 377

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-3108214	SUMOylation of DNA damage response and repair proteins

MSigDB gene sets: 138 (showing top): GOBP_CHROMOSOME_ORGANIZATION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_TELOMERE_ORGANIZATION, CHANDRAN_METASTASIS_DN, GOBP_REGULATION_OF_TELOMERE_MAINTENANCE, GOBP_PEPTIDYL_LYSINE_MODIFICATION, GOBP_PROTEIN_SUMOYLATION, GOBP_DNA_DAMAGE_RESPONSE, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, BERTUCCI_MEDULLARY_VS_DUCTAL_BREAST_CANCER_UP, FISCHER_DREAM_TARGETS, GOBP_REGULATION_OF_CHROMOSOME_ORGANIZATION, GTATGAT_MIR154_MIR487, GOBP_RECOMBINATIONAL_REPAIR

GO Biological Process (7): double-strand break repair via homologous recombination (GO:0000724), DNA repair (GO:0006281), DNA damage response (GO:0006974), protein sumoylation (GO:0016925), regulation of telomere maintenance (GO:0032204), chromatin looping (GO:0140588), DNA recombination (GO:0006310)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (6): chromosome, telomeric region (GO:0000781), nucleus (GO:0005634), nucleoplasm (GO:0005654), nuclear body (GO:0016604), Smc5-Smc6 complex (GO:0030915), chromosome (GO:0005694)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
SUMO E3 ligases SUMOylate target proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
DNA metabolic process	2
intracellular membraneless organelle	2
recombinational repair	1
double-strand break repair	1
DNA damage response	1
cellular response to stress	1
peptidyl-lysine modification	1
protein modification by small protein conjugation	1
telomere maintenance	1
regulation of chromosome organization	1
regulation of DNA metabolic process	1
chromatin organization	1
binding	1
chromosomal region	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cellular anatomical structure	1
nucleoplasm	1
condensed chromosome	1
SUMO ligase complex	1

Protein interactions and networks

STRING

704 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NSMCE4A	SMC6	Q96SB8	972
NSMCE4A	SMC5	Q8IY18	956
NSMCE4A	NSMCE3	Q96MG7	834
NSMCE4A	NSMCE1	Q8WV22	803
NSMCE4A	NSMCE2	Q96MF7	797
NSMCE4A	MAGEF1	Q9HAY2	552
NSMCE4A	RAD17	O75943	551
NSMCE4A	MAGEB18	Q96M61	515
NSMCE4A	RAD21	O60216	468
NSMCE4A	ANKRD16	Q6P6B7	459
NSMCE4A	EID2	Q8N6I1	435
NSMCE4A	MAIP1	Q8WWC4	426
NSMCE4A	EID2B	Q96D98	412
NSMCE4A	ATE1	O95260	397
NSMCE4A	SLF1	Q9BQI6	397

IntAct

64 interactions, top by confidence:

A	B	Type	Score
SMC6	SMC5	psi-mi:“MI:0914”(association)	0.860
NSMCE4A	NSMCE3	psi-mi:“MI:0915”(physical association)	0.820
NSMCE3	NSMCE4A	psi-mi:“MI:0915”(physical association)	0.820
NSMCE1	SMC5	psi-mi:“MI:0914”(association)	0.760
NSMCE1	SMC5	psi-mi:“MI:0915”(physical association)	0.760
NSMCE4A	NSMCE1	psi-mi:“MI:0914”(association)	0.740
BMAL2	CLOCK	psi-mi:“MI:0914”(association)	0.670
ZNF597	TASOR2	psi-mi:“MI:0914”(association)	0.640
BMAL2	CLOCK	psi-mi:“MI:0914”(association)	0.550
IER2	KPNA3	psi-mi:“MI:0914”(association)	0.530
TSPYL6	NME4	psi-mi:“MI:0914”(association)	0.530
ODAD3	CCDC22	psi-mi:“MI:0914”(association)	0.530
NSMCE1	PMF1	psi-mi:“MI:0914”(association)	0.530
PJA1	SMC5	psi-mi:“MI:0914”(association)	0.530
ZNF597	HCFC1	psi-mi:“MI:0914”(association)	0.530
NSMCE4A	SRPK2	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
SRPK1	NSMCE4A	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
Smc6	SMC5	psi-mi:“MI:0915”(physical association)	0.400
MAGEA1	NSMCE4A	psi-mi:“MI:0915”(physical association)	0.400
MAGED4B	NSMCE4A	psi-mi:“MI:0915”(physical association)	0.400
NSMCE4A	NDN	psi-mi:“MI:0915”(physical association)	0.400
NSMCE4A	PB2	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (108): NSMCE4A (Affinity Capture-MS), SMC6 (Affinity Capture-MS), NDNL2 (Affinity Capture-MS), SMC5 (Affinity Capture-MS), BRCA2 (Affinity Capture-MS), DNAJB2 (Affinity Capture-MS), NSMCE4A (Affinity Capture-MS), NSMCE4A (Affinity Capture-MS), NSMCE4A (Affinity Capture-MS), NSMCE4A (Affinity Capture-MS), NSMCE4A (Affinity Capture-MS), NSMCE4A (Two-hybrid), NSMCE4A (Affinity Capture-MS), NSMCE4A (Affinity Capture-MS), NSMCE4A (Affinity Capture-Western)

ESM2 similar proteins: A2AU37, A5LFW4, A6QPC8, A9SV60, A9SY64, B0BN28, C0SV12, C6KIE6, F4HZD1, F4JET1, F4K3G5, F4K487, K7TQE3, O65312, O82504, Q0V7M7, Q10SU5, Q13156, Q2RBJ4, Q2TBI1, Q3V124, Q4V3E2, Q4V8G2, Q56Y74, Q5RH01, Q6AUQ7, Q6S5G3, Q75PQ8, Q8H1E8, Q8N140, Q94HV8, Q9C5P0, Q9C5P1, Q9C689, Q9C6G0, Q9CPV1, Q9FJX9, Q9FKV5, Q9FT92, Q9LFQ9

Diamond homologs: A5LFW4, A6QPC8, P43124, Q2TBI1, Q3V124, Q4V8G2, Q8N140, Q9NXX6

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
NSMCE4A	“form complex”	SMC5/6	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 68 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
SUMOylation of DNA damage response and repair proteins	5	18.8×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
regulation of telomere maintenance	6	82.9×	2e-08
protein sumoylation	6	31.9×	4e-06
double-strand break repair via homologous recombination	8	20.5×	8e-07
DNA damage response	8	7.0×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	51
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1932 predictions. Top by Δscore:

Variant	Effect	Δscore
10:121960353:TTTA:T	donor_loss	1.0000
10:121960354:TTAC:T	donor_loss	1.0000
10:121960355:TA:T	donor_loss	1.0000
10:121960356:A:T	donor_loss	1.0000
10:121960357:CCTA:C	donor_gain	1.0000
10:121960402:CCATC:C	acceptor_gain	1.0000
10:121960403:CATC:C	acceptor_gain	1.0000
10:121960403:CATCC:C	acceptor_gain	1.0000
10:121960405:TC:T	acceptor_gain	1.0000
10:121960405:TCC:T	acceptor_loss	1.0000
10:121960406:CC:C	acceptor_gain	1.0000
10:121960407:C:CC	acceptor_gain	1.0000
10:121960407:CTA:C	acceptor_loss	1.0000
10:121960408:T:C	acceptor_loss	1.0000
10:121961420:TA:T	donor_loss	1.0000
10:121961421:A:AC	donor_gain	1.0000
10:121961421:AC:A	donor_gain	1.0000
10:121961422:C:CC	donor_gain	1.0000
10:121961422:C:CT	donor_loss	1.0000
10:121961422:CC:C	donor_gain	1.0000
10:121961514:TCAG:T	acceptor_gain	1.0000
10:121961515:CAG:C	acceptor_gain	1.0000
10:121961515:CAGC:C	acceptor_gain	1.0000
10:121961516:AG:A	acceptor_gain	1.0000
10:121961516:AGC:A	acceptor_loss	1.0000
10:121961517:GC:G	acceptor_loss	1.0000
10:121961518:C:CC	acceptor_gain	1.0000
10:121961518:C:CG	acceptor_loss	1.0000
10:121961519:T:A	acceptor_loss	1.0000
10:121961520:A:C	acceptor_gain	1.0000

AlphaMissense

2534 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:121961432:G:C	F310L	1.000
10:121961432:G:T	F310L	1.000
10:121961434:A:G	F310L	1.000
10:121971021:G:T	A140D	1.000
10:121971030:A:G	L137P	1.000
10:121971039:G:T	A134D	1.000
10:121971040:C:G	A134P	1.000
10:121971052:C:G	A130P	1.000
10:121974025:C:G	A117P	1.000
10:121974891:A:G	L92P	1.000
10:121960360:A:T	I329K	0.999
10:121960396:G:T	A317E	0.999
10:121961424:C:G	R313P	0.999
10:121961444:A:C	F306L	0.999
10:121961444:A:T	F306L	0.999
10:121961446:A:G	F306L	0.999
10:121967716:A:G	W198R	0.999
10:121967716:A:T	W198R	0.999
10:121970940:A:G	L167P	0.999
10:121970998:C:G	A148P	0.999
10:121971009:C:T	G144D	0.999
10:121971010:C:G	G144R	0.999
10:121971019:A:G	S141P	0.999
10:121971022:C:G	A140P	0.999
10:121971041:A:C	D133E	0.999
10:121971041:A:T	D133E	0.999
10:121971042:T:A	D133V	0.999
10:121971042:T:C	D133G	0.999
10:121971042:T:G	D133A	0.999
10:121971043:C:A	D133Y	0.999

dbSNP variants (sampled 300 via entrez): RS1000177926 (10:121969084 C>T), RS1000204531 (10:121958860 G>T), RS1000321136 (10:121959092 C>T), RS1000478740 (10:121966522 A>G), RS1000576419 (10:121963891 G>C,T), RS1000776105 (10:121966189 C>G), RS1001175563 (10:121975527 C>G,T), RS1001270035 (10:121969663 A>G), RS1001767906 (10:121974800 C>A,T), RS1001800448 (10:121974630 G>A), RS1001916507 (10:121957578 C>T), RS1001927138 (10:121969232 G>A), RS1002047903 (10:121964691 C>T), RS1002054780 (10:121963480 G>A,C), RS1002272631 (10:121971085 A>G)

Disease associations

OMIM: gene MIM:612987 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression	3
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
Cadmium Chloride	decreases expression	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
TAK-243	increases sumoylation	1
methylmercuric chloride	decreases expression	1
bisphenol A	decreases expression	1
arsenite	increases reaction, affects binding	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	decreases expression	1
cobaltous chloride	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
N,N,N’,N’-tetrakis(2-pyridylmethyl)ethylenediamine	decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
ICG 001	increases expression	1
3-(2-hydroxy-4-(2-methylnonan-2-yl)phenyl)cyclohexan-1-ol	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	decreases expression	1
Acetaminophen	decreases expression	1
Glyphosate	affects methylation	1
Atrazine	decreases expression	1
Benzo(a)pyrene	decreases methylation	1
Carbamazepine	affects expression	1
Dichlorodiphenyl Dichloroethylene	increases expression	1
Demecolcine	decreases expression	1
Dimethyl Sulfoxide	increases expression	1
Formaldehyde	decreases expression	1
Ivermectin	decreases expression	1
Lead	affects expression	1

Clinical trials (associated diseases)

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