TRAIP

Summary

TRAIP (TRAF interacting protein, HGNC:30764) is a protein-coding gene on chromosome 3p21.31, encoding E3 ubiquitin-protein ligase TRAIP (Q9BWF2). E3 ubiquitin ligase required to protect genome stability in response to replication stress. It is a selective cancer dependency (DepMap: 81.7% of cell lines).

This gene encodes a protein that contains an N-terminal RING finger motif and a putative coiled-coil domain. A similar murine protein interacts with TNFR-associated factor 1 (TRAF1), TNFR-associated factor 2 (TRAF2), and cylindromatosis. The interaction with TRAF2 inhibits TRAF2-mediated nuclear factor kappa-B, subunit 1 activation that is required for cell activation and protection against apoptosis.

Source: NCBI Gene 10293 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Seckel syndrome 9 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 17
• Clinical variants (ClinVar): 234 total — 12 pathogenic, 3 likely-pathogenic
• GTEx eGene: eQTL in 5 tissues, sQTL in 4 (q < 0.05)
• Phenotypes (HPO): 50
• Cancer dependency (DepMap): dependent in 81.7% of screened cell lines
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.74 (unconstrained)
• MANE Select transcript: NM_005879

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30764
Approved symbol	TRAIP
Name	TRAF interacting protein
Location	3p21.31
Locus type	gene with protein product
Status	Approved
Aliases	TRIP, RNF206
Ensembl gene	ENSG00000183763
Ensembl biotype	protein_coding
OMIM	605958
Entrez	10293

Gene structure

Transcript identifiers

Ensembl transcripts: 38 — 19 protein_coding, 13 nonsense_mediated_decay, 5 retained_intron, 1 protein_coding_CDS_not_defined

MANE Select: ENST00000331456

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

ENST00000331456, ENST00000469027, ENST00000473195, ENST00000473863, ENST00000475495, ENST00000477546, ENST00000482243, ENST00000482582, ENST00000488860, ENST00000489948, ENST00000491060, ENST00000891847, ENST00000891848, ENST00000929617, ENST00000929618, ENST00000929619, ENST00000929620, ENST00000929621, ENST00000929622, ENST00000929623, ENST00000929624, ENST00000929625, ENST00000967097, ENST00000967098, ENST00001031061, ENST00001073643, ENST00001073644, ENST00001073645, ENST00001073646, ENST00001073648, ENST00001073649, ENST00001073650, ENST00001073651, ENST00001073652, ENST00001073653, ENST00001073654, ENST00001073655, ENST00001143926

RefSeq mRNA: 1 — MANE Select: NM_005879 NM_005879

CCDS: CCDS2806

Canonical transcript exons

ENST00000331456 — 15 exons

Exon	Start	End
ENSE00001290242	49843801	49843928
ENSE00001291230	49841826	49841939
ENSE00001299748	49828601	49829225
ENSE00001309633	49842453	49842547
ENSE00001329595	49840985	49841072
ENSE00003471351	49829458	49829508
ENSE00003492851	49847525	49847608
ENSE00003514428	49840284	49840373
ENSE00003520695	49839772	49839860
ENSE00003547640	49856356	49856564
ENSE00003560221	49829617	49829766
ENSE00003613665	49844541	49844580
ENSE00003623604	49831916	49832068
ENSE00003657283	49848143	49848200
ENSE00003680642	49830020	49830068

Expression profiles

Bgee: expression breadth ubiquitous, 169 present calls, max score 88.53.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 5.3264 / max 91.0908, expressed in 1365 samples.

Highest expression (Bgee): male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, ventricular zone, ganglionic eminence, mucosa of transverse colon.

Genetic regulation across tissues (GTEx eQTL / sQTL)

TRAIP is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 5 tissues and its splicing (sQTL) in 4 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

9 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Testis	eqtl	2.5e-09	+0.23	3:49823245:C:T
Testis	sqtl	7.5e-08	+0.58	3:49856597:T:C
Skin Not Sun Exposed Suprapubic	eqtl	9.2e-04	+0.12	3:49904003:G:A
Esophagus Mucosa	sqtl	3.9e-03	-0.66	3:50240637:C:T
Cells Cultured fibroblasts	eqtl	1.4e-02	-0.13	3:50066721:G:A
Brain Frontal Cortex BA9	sqtl	1.9e-02	+0.45	3:50136751:C:T
Skin Sun Exposed Lower leg	eqtl	3.0e-02	-0.08	3:50085532:T:C
Cells EBV-transformed lymphocytes	sqtl	4.4e-02	-1.04	3:50820936:C:T
Brain Substantia nigra	eqtl	5.0e-02	+0.30	3:49666644:A:G

FANTOM5 promoters

2 alternative TSS:

Promoter ID	TPM avg	Samples expressed
42282	4.9886	1351
42281	0.3378	186

Top tissues by expression

showing 100 of 295 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	88.53	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	87.60	gold quality
ventricular zone	UBERON:0003053	84.85	gold quality
ganglionic eminence	UBERON:0004023	82.20	gold quality
mucosa of transverse colon	UBERON:0004991	80.38	gold quality
left testis	UBERON:0004533	79.63	gold quality
right testis	UBERON:0004534	79.15	gold quality
endometrium epithelium	UBERON:0004811	77.99	silver quality
testis	UBERON:0000473	77.30	gold quality
lower esophagus mucosa	UBERON:0035834	76.45	gold quality
stromal cell of endometrium	CL:0002255	75.68	gold quality
rectum	UBERON:0001052	75.37	gold quality
nucleus accumbens	UBERON:0001882	75.34	gold quality
right uterine tube	UBERON:0001302	74.75	gold quality
esophagus mucosa	UBERON:0002469	73.88	gold quality
embryo	UBERON:0000922	73.67	gold quality
cortical plate	UBERON:0005343	73.62	gold quality
granulocyte	CL:0000094	72.90	gold quality
skin of leg	UBERON:0001511	72.65	gold quality
skin of abdomen	UBERON:0001416	72.21	gold quality
ectocervix	UBERON:0012249	72.11	gold quality
hindlimb stylopod muscle	UBERON:0004252	71.92	gold quality
lymph node	UBERON:0000029	71.06	gold quality
body of uterus	UBERON:0009853	71.06	gold quality
transverse colon	UBERON:0001157	71.02	gold quality
adrenal tissue	UBERON:0018303	70.96	gold quality
calcaneal tendon	UBERON:0003701	70.86	gold quality
left ovary	UBERON:0002119	70.82	gold quality
right ovary	UBERON:0002118	70.47	gold quality
small intestine Peyer’s patch	UBERON:0003454	70.46	gold quality
secondary oocyte	CL:0000655	69.93	silver quality
esophagus	UBERON:0001043	69.70	gold quality
endocervix	UBERON:0000458	69.60	gold quality
gall bladder	UBERON:0002110	69.46	gold quality
muscle of leg	UBERON:0001383	69.44	gold quality
caudate nucleus	UBERON:0001873	69.39	gold quality
apex of heart	UBERON:0002098	69.24	gold quality
gastrocnemius	UBERON:0001388	68.99	gold quality
spleen	UBERON:0002106	68.99	gold quality
right hemisphere of cerebellum	UBERON:0014890	68.69	gold quality
zone of skin	UBERON:0000014	68.56	gold quality
putamen	UBERON:0001874	68.48	gold quality
smooth muscle tissue	UBERON:0001135	68.38	gold quality
cerebellar hemisphere	UBERON:0002245	68.30	gold quality
muscle layer of sigmoid colon	UBERON:0035805	68.18	gold quality
cerebellar cortex	UBERON:0002129	68.09	gold quality
right adrenal gland	UBERON:0001233	67.99	gold quality
right adrenal gland cortex	UBERON:0035827	67.83	gold quality
small intestine	UBERON:0002108	67.56	gold quality
ovary	UBERON:0000992	67.55	gold quality
body of stomach	UBERON:0001161	67.36	gold quality
minor salivary gland	UBERON:0001830	67.14	gold quality
islet of Langerhans	UBERON:0000006	67.08	gold quality
prefrontal cortex	UBERON:0000451	66.98	gold quality
left adrenal gland	UBERON:0001234	66.95	gold quality
mucosa of stomach	UBERON:0001199	66.93	gold quality
vagina	UBERON:0000996	66.76	gold quality
tibial nerve	UBERON:0001323	66.72	gold quality
left adrenal gland cortex	UBERON:0035825	66.55	gold quality
right frontal lobe	UBERON:0002810	66.54	gold quality
left lobe of thyroid gland	UBERON:0001120	66.49	gold quality
vermiform appendix	UBERON:0001154	66.45	gold quality
intestine	UBERON:0000160	66.32	gold quality
colon	UBERON:0001155	66.11	gold quality
bone marrow cell	CL:0002092	66.01	gold quality
large intestine	UBERON:0000059	65.85	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	65.81	gold quality
cerebellum	UBERON:0002037	65.78	gold quality
popliteal artery	UBERON:0002250	65.69	gold quality
tibial artery	UBERON:0007610	65.69	gold quality
metanephros cortex	UBERON:0010533	65.66	gold quality
tendon	UBERON:0000043	65.65	gold quality
thyroid gland	UBERON:0002046	65.64	gold quality
body of pancreas	UBERON:0001150	65.59	gold quality
ascending aorta	UBERON:0001496	65.55	gold quality
thoracic aorta	UBERON:0001515	65.54	gold quality
aorta	UBERON:0000947	65.49	gold quality
stomach	UBERON:0000945	65.46	gold quality
adrenal gland	UBERON:0002369	65.32	gold quality
monocyte	CL:0000576	65.31	gold quality
leukocyte	CL:0000738	65.30	gold quality
lower esophagus	UBERON:0013473	65.25	gold quality
lower esophagus muscularis layer	UBERON:0035833	65.18	gold quality
mononuclear cell	CL:0000842	65.16	gold quality
left coronary artery	UBERON:0001626	65.14	gold quality
sigmoid colon	UBERON:0001159	65.13	gold quality
pancreas	UBERON:0001264	65.08	gold quality
cingulate cortex	UBERON:0003027	65.05	gold quality
left uterine tube	UBERON:0001303	65.04	gold quality
adrenal cortex	UBERON:0001235	64.97	gold quality
ileal mucosa	UBERON:0000331	64.95	silver quality
anterior cingulate cortex	UBERON:0009835	64.89	gold quality
right lobe of thyroid gland	UBERON:0001119	64.82	gold quality
subcutaneous adipose tissue	UBERON:0002190	64.78	gold quality
adenohypophysis	UBERON:0002196	64.78	gold quality
oocyte	CL:0000023	64.66	silver quality
Brodmann (1909) area 9	UBERON:0013540	64.66	gold quality
right atrium auricular region	UBERON:0006631	64.46	gold quality
muscle organ	UBERON:0001630	64.36	gold quality
descending thoracic aorta	UBERON:0002345	64.30	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	3.95

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Putamen	tissue	14.2
Basal ganglia	tissue	13.4	not detected
Ventral forebrain	tissue	10.8
Septum	tissue	7.1
Bone marrow	tissue	6.4	medium
Testis	tissue	5.7	high
Nucleus accumbens	tissue	5.1
Thymus	tissue	5.0
Lymph node	tissue	4.3	low
Tonsil	tissue	4.1	medium
Skin 1	tissue	4.0	low
Substantia nigra	tissue	3.9
Caudate putamen	tissue	3.7
Amygdala	tissue	3.6
Hippocampal formation	tissue	3.3
Cerebral cortex	tissue	2.7	medium
Rectum	tissue	2.7	high
Entorhinal cortex	tissue	2.7
Olfactory bulb	tissue	2.7
Temporal cortex	tissue	2.7
Insular cortex	tissue	2.5
Prefrontal cortex	tissue	2.4
Motor cortex	tissue	2.4
Ovary	tissue	2.3	low
Hippocampus	tissue	2.3	not detected
Occipital cortex	tissue	2.3
Colon	tissue	2.2	high
Somatosensory cortex	tissue	2.2
Retina	tissue	2.1
Frontal cortex	tissue	2.1
Smooth muscle	tissue	2.0	medium
Retrosplenial and cingulate cortex	tissue	2.0
Vagina	tissue	1.9	medium
Small intestine	tissue	1.9	medium
Retrosplenial cortex	tissue	1.9
Breast	tissue	1.8	medium
Skeletal muscle	tissue	1.8	medium
Esophagus	tissue	1.7	medium
Thalamus	tissue	1.7
Hypothalamus	tissue	1.7
Spinal cord	tissue	1.7
Corpus callosum	tissue	1.7
Fallopian tube	tissue	1.7	high
Appendix	tissue	1.7	medium
Endometrium 1	tissue	1.6	medium
Placenta	tissue	1.5	high
Midbrain	tissue	1.4
Duodenum	tissue	1.4	medium
Pons	tissue	1.3
Epididymis	tissue	1.3	medium
Medulla oblongata	tissue	1.3
Superior colliculi	tissue	1.3
Thyroid gland	tissue	1.3	medium
Postcentral gyrus	tissue	1.3
Pituitary gland	tissue	1.2
Spleen	tissue	1.2	not detected
Locus coeruleus	tissue	1.2
Periaqueductal gray	tissue	1.2
Stomach 1	tissue	1.1	medium
Tongue	tissue	1.1

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Caudate nucleus (5.1), Nucleus basalis of Meynert (4.5), Ventral hippocampus (3.3), Dorsal hippocampus (3.2), Hippocampus, CA1 (3.2).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

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

23 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-7152-3P	99.97	67.47	849
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-3151-5P	99.86	63.83	1069
HSA-MIR-8073	99.86	65.21	1118
HSA-MIR-762	99.58	66.61	1994
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-940	99.37	66.14	2064
HSA-MIR-6808-5P	99.31	66.23	2150
HSA-MIR-6893-5P	99.31	66.25	2119
HSA-MIR-5001-5P	99.05	66.76	1972
HSA-MIR-3190-5P	98.87	64.89	1345
HSA-MIR-6511B-5P	97.98	65.64	823
HSA-MIR-6811-5P	97.98	64.96	848
HSA-MIR-6893-3P	97.79	64.91	1238
HSA-MIR-6769B-3P	97.41	65.53	1036
HSA-MIR-10397-5P	97.31	69.06	710
HSA-MIR-4433B-3P	97.22	63.62	663
HSA-MIR-370-3P	97.09	64.92	1221
HSA-MIR-1587	96.95	64.03	932
HSA-MIR-4281	92.91	63.60	271

Functional genomics

gnomAD constraint: pLI 1.78e-06, LOEUF 0.739, missense Z 1.87 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000331456 — one region, missense o/e 0.83. DepMap (CRISPR cell-line fitness): dependent in 81.7% of screened cell lines.

Most-dependent cell lines (DepMap gene-effect, lower = stronger; ≤ −0.5 shown): SK-MM-2 (-2.086), COR-L311 (-1.945), DB (-1.908), NCI-H1694 (-1.891), GSU (-1.882), GCIY (-1.795), NCI-H522 (-1.784), MG-63 (-1.729), MHH-ES-1 (-1.711), YAPC (-1.622), BICR 31 (-1.607), OAW28 (-1.587), HCC1187 (-1.58), KMS-34 (-1.557), NCI-H209 (-1.551).

Literature-anchored findings (GeneRIF, showing 26)

• CYLD interacts with TRIP and regulates negatively nuclear factor kappaB activation by tumor necrosis factor. (PMID:14676304)
• The overexpression of TRIP sensitizes cells to TNF-induced apoptosis, an effect that can be reversed by the coexpression of Syk. (PMID:19151749)
• The TRAF-interacting protein (TRIP) is a regulator of keratinocyte proliferation. (PMID:21068752)
• observed enhanced ubiquitylation of Poleta by TRIP E3 ligase and show that TRIP promotes Poleta localization to nuclear foci (PMID:24553286)
• The TRAIP ubiquitin ligase activity is functionally required for the spindle assembly checkpoint control. (PMID:25335891)
• Data indicate that TRAF interacting protein TRIP negatively regulates the TNFR-associated factor 2 (TRAF2) ubiquitin-dependent pathway by modulating the TRAF2-sphingosine 1-phosphate (S1P) interaction. (PMID:25716317)
• a number of TRAIP mutants were used to define the TRAIP molecular domains responsible for its homo-dimerization. A co-immunoprecipitation assay indicated that the TRAIP forms homo-dimerization through the CC domain (PMID:26093298)
• cell cycle-dependent transcription of the TRAIP gene by E2F1, E2F2, and E2F4 and rapid protein degradation leads to cell cycle-dependent expression with a maximum in G2/M (PMID:26369285)
• TRAIP is a component of the DNA damage response to replication-blocking DNA lesions.TRAIP promotes DNA damage response during genome replication and is mutated in primordial dwarfism. (PMID:26595769)
• These findings establish TRAIP as a PCNA-binding ubiquitin ligase with an important role in protecting genome integrity after obstacles to DNA replication. (PMID:26711499)
• TRAIP/RNF206 is required for recruitment of RAP80 to sites of DNA damage.( (PMID:26781088)
• Taken together, these findings improve the understanding clinical implication of TRAIP in various diseases including primordial dwarfism and cancers. (PMID:26820530)
• TRIP interacts with transforming growth factor beta-activated kinase 1 (TAK1) and promotes K48-linked polyubiquitination of TAK1 in rheumatoid arthritis fibroblast-Like synoviocytes (PMID:27847407)
• The TRAIP coiled-coil domain altered its stoichiometry between dimer and trimer in a concentration-dependent manner. Additionally, the TRAIP RING domain induced even higher-ordered assembly, which was necessary for interacting with the TRAF-N domain of TRAF2 but not TRAF1. (PMID:30127245)
• Nucleolar residence of the Seckel syndrome protein TRAIP is coupled to ribosomal DNA transcription. (PMID:30165463)
• present results, together with other recent findings, establish TRAIP as a master regulator of DNA helicase CMG unloading and the response of the replisome to obstacles (PMID:30842657)
• hese results suggest that TRAIP is a novel regulator of H2B monoubiquitination in DNA damage response and cancer development in lung adenocarcinoma. (PMID:30942468)
• TRAIP promotes malignant behaviors and correlates with poor prognosis in liver cancer. (PMID:31972358)
• TRAIP is important for the recruitment of NEIL3 but not FANCD2, and knockdown of TRAIP promotes FA/BRCA pathway activation. Interestingly, TRAIP is non-epistatic with both NEIL3 and FA pathways in psoralen-ICL repair, suggesting that TRAIP may function upstream of the two pathways. (PMID:31980815)
• TRIP suppresses cell proliferation and invasion in choroidal melanoma via promoting the proteasomal degradation of Twist1. (PMID:32640040)
• The Ubiquitin Ligase TRAIP: Double-Edged Sword at the Replisome. (PMID:33317933)
• TRAIP modulates the IGFBP3/AKT pathway to enhance the invasion and proliferation of osteosarcoma by promoting KANK1 degradation. (PMID:34349117)
• Silencing TRAIP suppresses cell proliferation and migration/invasion of triple negative breast cancer via RB-E2F signaling and EMT. (PMID:36064576)
• ZNF212 promotes genomic integrity through direct interaction with TRAIP. (PMID:36594163)
• TRAIP resolves DNA replication-transcription conflicts during the S-phase of unperturbed cells. (PMID:37604812)
• TRAIP suppressed apoptosis and cell cycle to promote prostate cancer proliferation via TRAF2-PI3K-AKT pathway activation. (PMID:38100027)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	traip	ENSDARG00000011262
mus_musculus	Traip	ENSMUSG00000032586
rattus_norvegicus	Traip	ENSRNOG00000030101

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1096377) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 7 distinct phenotype terms.

Mouse phenotype (MP)	Records
decreased cell proliferation	1
decreased embryo size	1
abnormal embryonic tissue morphology	1
embryonic growth retardation	1
embryonic lethality between somite formation and embryo turning, complete penetrance	1
absent proamniotic cavity	1
increased embryonic tissue cell apoptosis	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	Q4R6Y5	91.3%	Diamond
Xenopus laevis	Q6NRV0	56.4%	Diamond
Caenorhabditis elegans	P90990	48.8%	Diamond
Arabidopsis thaliana	O82239	44.0%	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
CDHR4	protein-coding	389118
INKA1	protein-coding	389119
UBA7	protein-coding	7318
CAMKV	protein-coding	79012
MIR5193	ncRNA	100847079
MST1R	protein-coding	4486
IP6K1	protein-coding	9807
MON1A	protein-coding	84315

Protein

Protein identifiers

E3 ubiquitin-protein ligase TRAIP — Q9BWF2 (reviewed: Q9BWF2)

Alternative names: RING finger protein 206, TRAF-interacting protein

All UniProt accessions (5): E7EN91, E7ETV1, E7EVC4, E7EW89, Q9BWF2

UniProt curated annotations — full annotation on UniProt →

Function. E3 ubiquitin ligase required to protect genome stability in response to replication stress. Acts as a key regulator of interstrand cross-link repair, which takes place when both strands of duplex DNA are covalently tethered together, thereby blocking replication and transcription. Controls the choice between the two pathways of replication-coupled interstrand-cross-link repair by mediating ubiquitination of MCM7 subunit of the CMG helicase complex. Short ubiquitin chains on MCM7 promote recruitment of DNA glycosylase NEIL3. If the interstrand cross-link cannot be cleaved by NEIL3, the ubiquitin chains continue to grow on MCM7, promoting the unloading of the CMG helicase complex by the VCP/p97 ATPase, enabling the Fanconi anemia DNA repair pathway. Only catalyzes ubiquitination of MCM7 when forks converge. Also involved in the repair of covalent DNA-protein cross-links (DPCs) during DNA synthesis: promotes ubiquitination of DPCs, leading to their degradation by the proteasome. Has also been proposed to play a role in promoting translesion synthesis by mediating the assembly of ‘Lys-63’-linked poly-ubiquitin chains on the Y-family polymerase POLN in order to facilitate bypass of DNA lesions and preserve genomic integrity. The function in translesion synthesis is however controversial. Acts as a regulator of the spindle assembly checkpoint. Also acts as a negative regulator of innate immune signaling by inhibiting activation of NF-kappa-B mediated by TNF. Negatively regulates TLR3/4- and RIG-I-mediated IRF3 activation and subsequent IFNB1 production and cellular antiviral response by promoting ‘Lys-48’-linked polyubiquitination of TNK1 leading to its proteasomal degradation.

Subunit / interactions. Interacts (via PIP-box) with PCNA. Binds TRAF1, TRAF2, TRAF3, TRAF5 and TRAF6 is part of the receptor-TRAF signaling complex. May interact with CYLD; the C-terminus interacts with CYLD, however the interaction was not detected with the full-length protein. Interacts with POLK and POLN. Interacts with UIMC1.

Subcellular location. Nucleus. Nucleoplasm. Nucleolus. Chromosome. Cytoplasm. Perinuclear region.

Post-translational modifications. Sumoylated; sumoylation is required for nuclear localization. Sumoylation increases protein stability, possibly by preventing ubiquitination. Autoubiquitinated.

Disease relevance. Seckel syndrome 9 (SCKL9) [MIM:616777] A form of Seckel syndrome, a rare autosomal recessive disorder characterized by proportionate dwarfism of prenatal onset associated with low birth weight, growth retardation, severe microcephaly with a bird-headed like appearance, and intellectual disability. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Protein modification; protein ubiquitination.

Similarity. Belongs to the TRAIP family.

RefSeq proteins (1): NP_005870* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001841	Znf_RING	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR052639	TRAIP_ubiq-protein_ligase	Family

Pfam: PF13639

UniProt features (22 total): mutagenesis site 9, sequence conflict 4, coiled-coil region 2, chain 1, zinc finger region 1, region of interest 1, helix 1, short sequence motif 1, cross-link 1, sequence variant 1

Structure

Experimental structures (PDB)

1 structures by resolution:

PDB	Title	Method	Resolution (Å)
4ZTD	Crystal Structure of Human PCNA in complex with a TRAIP peptide	X-RAY DIFFRACTION	2.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BWF2-F1	75.24	0.48

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Transferases, Predicted intracellular proteins, Disease related genes, Potential drug targets, Human disease related genes, Congenital malformations, Other congenital malformations, Essential proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cytosol; plasma membrane

Antibody reliability (HPA): IH enhanced · 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.

Post-translational modifications (1)

Type	Positions
Glycyl lysine isopeptide (lys-gly) (interchain with g-cter in sumo2)	304

Mutagenesis-validated functional residues (9)

Position	Phenotype
80	abolished sumoylation and localization to the nucleus; when associated with a-127, a-205, a-247 and a-462.
127	abolished sumoylation and localization to the nucleus; when associated with a-80, a-205, a-247 and a-462.
205	abolished sumoylation and localization to the nucleus; when associated with a-80, a-127, a-247 and a-462.
247	abolished sumoylation and localization to the nucleus; when associated with a-80, a-127, a-205 and a-462.
460–463	abolished interaction with pcna and localization to dna damage sites.
462	abolished sumoylation and localization to the nucleus; when associated with a-80, a-127, a-205 and a-247.
466	abolished interaction with pcna.
7	abolished accumulation in nucleolus.
25	abolished ability to regulate nuclear envelope breakdown to anaphase.

Function

Pathways and Gene Ontology

Reactome pathways

1 curated (TAS) of 4; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

4 pathways:

ID	Pathway	Evidence
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation	curated
R-HSA-1280218	Adaptive Immune System	—
R-HSA-983169	Class I MHC mediated antigen processing & presentation	—
R-HSA-168256	Immune System	—

MSigDB gene sets: 297 (showing top): GSE45365_NK_CELL_VS_CD11B_DC_UP, GOBP_DNA_TEMPLATED_DNA_REPLICATION_MAINTENANCE_OF_FIDELITY, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_RESPONSE_TO_PEPTIDE, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, CROONQUIST_NRAS_SIGNALING_DN, GOBP_NEGATIVE_REGULATION_OF_TYPE_I_INTERFERON_PRODUCTION, GOBP_NEGATIVE_REGULATION_OF_TUMOR_NECROSIS_FACTOR_MEDIATED_SIGNALING_PATHWAY, PATIL_LIVER_CANCER, MUELLER_PLURINET, CAGCAGG_MIR370, GOBP_NEGATIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS, MODULE_205, DOANE_RESPONSE_TO_ANDROGEN_DN

GO Biological Process (9): apoptotic process (GO:0006915), DNA damage response (GO:0006974), signal transduction (GO:0007165), negative regulation of tumor necrosis factor-mediated signaling pathway (GO:0010804), protein ubiquitination (GO:0016567), replication fork processing (GO:0031297), negative regulation of interferon-beta production (GO:0032688), protein-DNA covalent cross-linking repair (GO:0106300), DNA repair (GO:0006281)

GO Molecular Function (7): ubiquitin-protein transferase activity (GO:0004842), zinc ion binding (GO:0008270), identical protein binding (GO:0042802), ubiquitin protein ligase activity (GO:0061630), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (8): nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), plasma membrane (GO:0005886), perinuclear region of cytoplasm (GO:0048471), site of DNA damage (GO:0090734), chromosome (GO:0005694), cytoplasm (GO:0005737)

Reactome top-level categories

3 top-level categories:

Category	Pathways
Class I MHC mediated antigen processing & presentation	1
Immune System	1
Adaptive Immune System	1

GO top-level categories

37 GO namespaces:

Category	Terms
cellular anatomical structure	4
nuclear lumen	2
intracellular membraneless organelle	2
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
cellular response to stress	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
negative regulation of cytokine-mediated signaling pathway	1
regulation of tumor necrosis factor-mediated signaling pathway	1
tumor necrosis factor-mediated signaling pathway	1
protein modification by small protein conjugation	1
DNA-templated DNA replication maintenance of fidelity	1
negative regulation of type I interferon production	1
interferon-beta production	1
regulation of interferon-beta production	1
DNA repair	1
DNA metabolic process	1
DNA damage response	1
ubiquitin-like protein transferase activity	1
transition metal ion binding	1
protein binding	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
binding	1
catalytic activity	1
cation binding	1
intracellular membrane-bounded organelle	1
membrane	1
cell periphery	1
cytoplasm	1
chromosome	1
intracellular anatomical structure	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 10 of 24 annotations. The rest are phylogenetic / computational / electronic (IEA).

10 experimentally-supported GO terms:

GO term	NS	Evidence
DNA damage response	BP	direct assay
negative regulation of tumor necrosis factor-mediated signaling pathway	BP	direct assay
protein ubiquitination	BP	direct assay
replication fork processing	BP	direct assay
nucleolus	CC	direct assay
nucleoplasm	CC	direct assay
plasma membrane	CC	direct assay
site of DNA damage	CC	direct assay
identical protein binding	MF	physical interaction
ubiquitin-protein transferase activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 990 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TRAIP	NEIL3	Q8TAT5	717
TRAIP	CYLD	Q9NQC7	634
TRAIP	LRR1	Q96L50	633
TRAIP	SPRTN	Q9H040	630
TRAIP	FANCD2	Q9BXW9	612
TRAIP	CDC45	O75419	609
TRAIP	TRADD	Q15628	570
TRAIP	TRAF1	Q13077	563
TRAIP	TNFRSF8	P28908	557
TRAIP	SLX4	Q8IY92	546
TRAIP	MCM7	P33993	535
TRAIP	MUS81	Q96NY9	522
TRAIP	EME1	Q96AY2	520
TRAIP	FANCM	Q8IYD8	509
TRAIP	UBXN7	O94888	504

IntAct

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

23 partners by confidence:

Partner	Interaction type	MIscore	Records
MAPRE2	physical association	0.780	10
ALOX15B	physical association	0.560	3
CEP19	physical association	0.560	3
JPH3	physical association	0.560	3
LXN	physical association	0.560	3
MAPRE3	physical association	0.560	3
POLR1C	physical association	0.560	3
UBE2K	physical association	0.560	3
NCK1	physical association	0.400	3
FYN	physical association	0.400	1
GRB2	physical association	0.400	1
PLCG1	physical association	0.400	1
HIP2	physical association	0.370	1
RNF114	physical association	0.370	1
RNF4	physical association	0.370	1
TRIM23	physical association	0.370	1
TRIM41	physical association	0.370	1
TSG101	physical association	0.370	1
UBE2H	physical association	0.370	1
UBE2U	physical association	0.370	1
UBE2Z	physical association	0.370	1
UBOX5	physical association	0.370	1
NME2	association	0.350	1

BioGRID (111 interactions; top human partners by supporting records): PCNA (Affinity Capture-Western; 7 records), TRAF2 (Affinity Capture-Western; 5 records), POLH (Two-hybrid; 4 records), UIMC1 (Two-hybrid; 4 records), SYK (Two-hybrid; 3 records), TRAF1 (Two-hybrid; 3 records), ZNF212 (Affinity Capture-Western; 3 records), CYLD (Two-hybrid; 2 records), FLII (Two-hybrid; 2 records), H2AFX (Co-localization; 2 records), MAPRE2 (Two-hybrid; 2 records), RNF20 (Affinity Capture-Western; 2 records), RNF40 (Affinity Capture-Western; 2 records), TBK1 (Affinity Capture-Western; 2 records), TRAF3 (Affinity Capture-Western; 2 records)

SIGNOR signaling

1 signaling interactions:

A	Effect	B	Mechanism
Ub:E2	“up-regulates activity”	TRAIP	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 23 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
Antigen processing: Ubiquitination & Proteasome degradation	8	17.5×	1e-06

GO biological processes:

GO term	Partners	Fold	FDR
protein polyubiquitination	5	26.2×	2e-04

Disease & clinical

Genetic variants

Variant evidence for TRAIP: 234 ClinVar records (15 pathogenic / likely pathogenic); 17 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	12
Likely pathogenic	3
Uncertain significance	87
Likely benign	95
Benign	17

Top pathogenic / likely-pathogenic (15)

Showing all 15 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
221232	NM_005879.3(TRAIP):c.553C>T (p.Arg185Ter)	Pathogenic	criteria provided, single submitter	2
2168671	NM_005879.3(TRAIP):c.836del (p.Asn279fs)	Pathogenic	criteria provided, single submitter	1
2698999	NM_005879.3(TRAIP):c.878del (p.Val292_Leu293insTer)	Pathogenic	criteria provided, single submitter	1
2810768	NM_005879.3(TRAIP):c.66_81dup (p.Thr28fs)	Pathogenic	criteria provided, single submitter	1
2989649	NM_005879.3(TRAIP):c.169del (p.Thr57fs)	Pathogenic	criteria provided, single submitter	1
2991455	NM_005879.3(TRAIP):c.301C>T (p.Gln101Ter)	Pathogenic	criteria provided, single submitter	1
2998164	NM_005879.3(TRAIP):c.349del (p.Thr117fs)	Pathogenic	criteria provided, single submitter	1
3646873	NM_005879.3(TRAIP):c.724G>T (p.Glu242Ter)	Pathogenic	criteria provided, single submitter	1
3698997	NM_005879.3(TRAIP):c.654_655del (p.Glu220fs)	Pathogenic	criteria provided, single submitter	1
2119077	NM_005879.3(TRAIP):c.796-2A>G	Likely pathogenic	criteria provided, single submitter	1
3067877	NM_005879.3(TRAIP):c.1093C>T (p.Gln365Ter)	Likely pathogenic	criteria provided, single submitter	1
4696593	NM_005879.3(TRAIP):c.98+2T>G	Likely pathogenic	criteria provided, single submitter	1
2425431	NC_000003.11:g.(?49877205)(49882013_?)del	Pathogenic	criteria provided, single submitter	1
221233	NM_005879.3(TRAIP):c.52C>T (p.Arg18Cys)	Pathogenic	no assertion criteria provided	1
4819264	P47L	Pathogenic	no assertion criteria provided	1

Per-variant reference — Sugi Variant

Explore TRAIP’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; 40 predictions of 1,498):

Position(s)	Effect	Δscore	Sites
3:49839862	acceptor_gain	1.0000
3:49856354–49856355	donor_loss	1.0000	3
3:49829509–49829510	acceptor_loss	0.9900	6
3:49830018–49830019	donor_loss	0.9900	5
3:49830069–49830070	acceptor_loss	0.9900	6
3:49839770–49839771	donor_loss	0.9900	5
3:49847523–49847524	donor_loss	0.9900	5
3:49848201–49848202	acceptor_loss	0.9900	6
3:49856355	donor_loss	0.9900	2
3:49829810	acceptor_gain	0.9800

AlphaMissense

673 missense substitutions predicted likely pathogenic (of 3,080 scored), across 213 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
H27	8	0.997	0.999
H30	8	0.991	0.998
F29	8	0.983	1.000
F64	8	0.983	0.996
F14	8	0.971	0.995
D12	8	0.950	0.988
F38	8	0.924	0.984
N81	8	0.882	0.961
D15	8	0.878	0.944
D19	8	0.864	0.954
D65	8	0.864	0.923
C7	7	0.998	0.999
C46	7	0.998	0.999
C10	7	0.997	0.999
C25	7	0.997	0.999
C49	7	0.997	0.999
C33	7	0.996	0.999
W37	7	0.996	0.999
F63	7	0.987	0.998
I9	7	0.943	0.998

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
Liver Hepatocellular Carcinoma (TCGA)	unfavorable	6.33e-08
Kidney Renal Clear Cell Carcinoma (TCGA)	unfavorable	6.86e-07
Liver Hepatocellular Carcinoma (validation)	unfavorable	9.26e-07
Lung Adenocarcinoma (TCGA)	unfavorable	0.000297
Kidney Renal Clear Cell Carcinoma (validation)	unfavorable	0.000661
Pancreatic Adenocarcinoma (validation)	unfavorable	0.000957

Disease associations

OMIM: gene MIM:605958 | disease phenotypes: MIM:616777

GenCC curated gene-disease

2 curated gene-disease records:

Disease	Classification	Inheritance	Records
Seckel syndrome 9	Strong	Autosomal recessive	3
Seckel syndrome	Supportive	Autosomal recessive

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (7 panels, 7 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

7 panels:

Panel	Rating
DDG2P	green
Fetal anomalies	green
Hypotonic infant	green
Intellectual disability	green
Leukodystrophy, childhood onset	green
Paediatric disorders	green
Severe microcephaly	green

Mondo (2): Seckel syndrome 9 (MONDO:0014767), Seckel syndrome (MONDO:0019342)

Orphanet (1): Seckel syndrome (Orphanet:808)

HPO phenotypes

50 phenotypes (HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000010	Recurrent urinary tract infections
HP:0000062	Ambiguous genitalia
HP:0000252	Microcephaly
HP:0000268	Dolichocephaly
HP:0000275	Narrow face
HP:0000276	Long face
HP:0000347	Micrognathia
HP:0000363	Abnormal earlobe morphology
HP:0000387	Absent earlobe
HP:0000411	Protruding ear
HP:0000444	Convex nasal ridge
HP:0000494	Downslanted palpebral fissures
HP:0000501	Glaucoma
HP:0000682	Abnormal dental enamel morphology
HP:0000776	Congenital diaphragmatic hernia
HP:0000998	Hypertrichosis
HP:0001249	Intellectual disability
HP:0001263	Global developmental delay
HP:0001363	Craniosynostosis
HP:0001382	Joint hypermobility
HP:0001385	Hip dysplasia
HP:0001511	Intrauterine growth retardation
HP:0001518	Small for gestational age
HP:0001558	Decreased fetal movement
HP:0001561	Polyhydramnios
HP:0001629	Ventricular septal defect
HP:0001631	Atrial septal defect
HP:0001762	Talipes equinovarus
HP:0001852	Sandal gap
HP:0002099	Asthma
HP:0002119	Ventriculomegaly
HP:0002205	Recurrent respiratory infections
HP:0002209	Sparse scalp hair
HP:0002650	Scoliosis
HP:0002750	Delayed skeletal maturation
HP:0004209	Clinodactyly of the 5th finger
HP:0004322	Short stature
HP:0004326	Cachexia
HP:0004971	Pulmonary artery hypoplasia
HP:0007495	Prematurely aged appearance
HP:0008633	Agonadism
HP:0008665	Clitoral hypertrophy
HP:0009804	Tooth agenesis
HP:0009879	Simplified gyral pattern
HP:0010579	Cone-shaped epiphysis
HP:0011342	Mild global developmental delay
HP:0011461	Fetal onset
HP:0030799	Scaphocephaly
HP:0100543	Cognitive impairment

GWAS associations

17 associations:

Study	Trait	p-value
GCST010698_7	Subcortical volume (min-P)	3e-24
GCST010701_11	Cortical surface area (MOSTest)	1e-16
GCST010002_422	Refractive error	4e-14
GCST010703_214	Brain morphology (MOSTest)	2e-13
GCST005316_336	Intelligence (MTAG)	2e-11
GCST010702_18	Subcortical volume (MOSTest)	1e-10
GCST011122_17	Walking pace	3e-10
GCST009524_157	Household income (MTAG)	4e-10
GCST012332_38	Multisite chronic pain	4e-10
GCST006920_7	Regular attendance at a gym or sports club	6e-10
GCST007614_9	C-reactive protein levels	6e-10
GCST008549_5	Mental health study participation (provided email address)	2e-8
GCST006922_9	Regular attendance at a religious group	3e-8
GCST007559_12	Sleep duration (short sleep)	3e-8
GCST007044_11	Extremely high intelligence	4e-8
GCST010699_3	Brain morphology (min-P)	4e-8
GCST008529_37	Tea consumption	9e-8

EFO canonical traits (from GWAS)

8 canonical traits:

EFO ID	Trait name
EFO:0004337	intelligence
EFO:0009592	social interaction measurement
EFO:0004458	C-reactive protein measurement
EFO:0010091	tea consumption measurement
EFO:0010130	health study participation
EFO:0009695	household income
EFO:0004346	neuroimaging measurement
EFO:0010100	multisite chronic pain

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression, decreases methylation, increases expression, increases methylation	4
Acetaminophen	decreases expression, increases expression	2
Tobacco Smoke Pollution	decreases expression, increases expression	2
aristolochic acid I	increases expression	1
TAK-243	increases sumoylation	1
bisphenol A	decreases expression	1
geraniol	decreases expression	1
2,2’-methylenebis(4-methyl-6-tert-butylphenol)	affects expression, affects response to substance	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	increases expression	1
zinc chromate	decreases expression, increases abundance	1
chromium hexavalent ion	decreases expression, increases abundance	1
perfluorooctane sulfonic acid	increases expression	1
2-palmitoylglycerol	increases expression	1
jinfukang	increases expression	1
Sunitinib	decreases expression	1
Zoledronic Acid	increases expression	1
Cadmium	decreases expression, increases abundance	1
Caffeine	decreases phosphorylation	1
Calcitriol	decreases expression, affects cotreatment	1
Cisplatin	increases expression	1
Dichlorodiphenyl Dichloroethylene	increases expression	1
Estradiol	decreases expression	1
Ethyl Methanesulfonate	increases expression	1
Folic Acid	affects expression	1
Gallic Acid	decreases expression	1
Menthol	decreases expression	1
Methyl Methanesulfonate	increases expression	1
Rotenone	decreases expression	1
Testosterone	decreases expression, affects cotreatment	1

Clinical trials (associated diseases)

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

1 trials:

NCT	Phase	Status	Title
NCT03139903	Not specified	COMPLETED	The Primordial Dwarfisms: Diagnosis, Identification of the Molecular Basis of Seckel Syndrome and Microcephalic Osteodysplastic Primordial Dwarfism Type II