TERF2

Summary

TERF2 (telomeric repeat binding factor 2, HGNC:11729) is a protein-coding gene on chromosome 16q22.1, encoding Telomeric repeat-binding factor 2 (Q15554). Binds the telomeric double-stranded 5’-TTAGGG-3’ repeat and plays a central role in telomere maintenance and protection against end-to-end fusion of chromosomes. It is a common-essential gene (DepMap: required in 96.5% of cancer cell lines).

This gene encodes a telomere specific protein, TERF2, which is a component of the telomere nucleoprotein complex. This protein is present at telomeres in metaphase of the cell cycle, is a second negative regulator of telomere length and plays a key role in the protective activity of telomeres. While having similar telomere binding activity and domain organization, TERF2 differs from TERF1 in that its N terminus is basic rather than acidic.

Source: NCBI Gene 7014 — RefSeq curated summary.

At a glance

• GWAS associations: 6
• Clinical variants (ClinVar): 68 total
• Regional missense constraint (gnomAD): 1 of 6 regions constrained (≈2% of expected missense variation)
• GTEx eGene: eQTL in 30 tissues, sQTL in 1 (q < 0.05)
• Cancer dependency (DepMap): dependent in 96.5% of screened cell lines (common-essential)
• Constraint (gnomAD): pLI 1.00 (loss-of-function intolerant), LOEUF 0.44 (moderately constrained)
• MANE Select transcript: NM_005652
• Notable: 68 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11729
Approved symbol	TERF2
Name	telomeric repeat binding factor 2
Location	16q22.1
Locus type	gene with protein product
Status	Approved
Aliases	TRF2
Ensembl gene	ENSG00000132604
Ensembl biotype	protein_coding
OMIM	602027
Entrez	7014

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 17 protein_coding, 4 nonsense_mediated_decay, 1 retained_intron, 1 protein_coding_CDS_not_defined

MANE Select: ENST00000254942

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

ENST00000254942, ENST00000564982, ENST00000566051, ENST00000566257, ENST00000566750, ENST00000567130, ENST00000567296, ENST00000567841, ENST00000569280, ENST00000569542, ENST00000569584, ENST00000569611, ENST00000903039, ENST00000930142, ENST00000966429, ENST00001022702, ENST00001022703, ENST00001022704, ENST00001022705, ENST00001084264, ENST00001084265, ENST00001113966, ENST00001132617

RefSeq mRNA: 1 — MANE Select: NM_005652 NM_005652

CCDS: CCDS10879

Canonical transcript exons

ENST00000254942 — 10 exons

Exon	Start	End
ENSE00000904612	69357518	69357561
ENSE00000904614	69361404	69361489
ENSE00000904616	69366807	69367199
ENSE00001141451	69355567	69357056
ENSE00003578666	69385391	69385486
ENSE00003638095	69370483	69370629
ENSE00003696379	69368376	69368482
ENSE00003704677	69384580	69384710
ENSE00003786702	69372269	69372355
ENSE00003842710	69385593	69386007

Expression profiles

Bgee: expression breadth ubiquitous, 293 present calls, max score 94.90.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 20.6660 / max 169.1686, expressed in 1815 samples.

Highest expression (Bgee): cortical plate, Brodmann (1909) area 46, sural nerve, ventricular zone, ganglionic eminence.

Genetic regulation across tissues (GTEx eQTL / sQTL)

TERF2 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 30 tissues and its splicing (sQTL) in 1 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 31 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Thyroid	eqtl	1.4e-38	-0.42	16:69368928:A:G
Esophagus Mucosa	eqtl	7.1e-09	-0.21	16:69368928:A:G
Brain Cerebellar Hemisphere	eqtl	1.0e-06	-0.27	16:69341938:C:T
Cells EBV-transformed lymphocytes	eqtl	1.7e-05	-0.21	16:69348292:A:G
Esophagus Muscularis	eqtl	1.7e-05	-0.14	16:69348292:A:G
Nerve Tibial	eqtl	2.2e-04	-0.12	16:69362682:C:T
Adipose Subcutaneous	eqtl	3.2e-04	-0.15	16:69241105:TCGC:T
Brain Cerebellum	eqtl	4.8e-04	-0.20	16:69366304:T:G
Brain Cortex	eqtl	9.9e-04	-0.22	16:69380016:C:T
Muscle Skeletal	eqtl	1.5e-03	-0.10	16:69385128:T:A
Skin Sun Exposed Lower leg	eqtl	1.7e-03	-0.10	16:69368928:A:G
Artery Tibial	eqtl	2.1e-03	-0.10	16:69375506:A:G
Adipose Visceral Omentum	eqtl	2.3e-03	-0.14	16:69362682:C:T
Heart Left Ventricle	eqtl	3.8e-03	-0.15	16:69375506:A:G
Ovary	eqtl	5.0e-03	-0.73	16:68508229:C:T
Skin Not Sun Exposed Suprapubic	eqtl	5.1e-03	-0.10	16:69390232:T:C
Small Intestine Terminal Ileum	eqtl	9.7e-03	-0.46	16:69322791:C:T
Cells Cultured fibroblasts	eqtl	1.1e-02	-0.08	16:69187607:C:G
Artery Aorta	eqtl	1.2e-02	-0.13	16:69331220:G:T
Brain Nucleus accumbens basal ganglia	eqtl	1.6e-02	-0.20	16:69398347:G:C

FANTOM5 promoters

7 alternative TSS:

Promoter ID	TPM avg	Samples expressed
157909	11.6005	1792
157907	4.6126	1648
157908	3.8048	1591
157906	0.2416	79
157905	0.2152	89
157903	0.1866	69
157904	0.0047	3

Top tissues by expression

showing 100 of 298 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	94.90	gold quality
Brodmann (1909) area 46	UBERON:0006483	93.88	gold quality
sural nerve	UBERON:0015488	93.86	gold quality
ventricular zone	UBERON:0003053	93.77	gold quality
ganglionic eminence	UBERON:0004023	92.50	gold quality
postcentral gyrus	UBERON:0002581	92.08	gold quality
colonic epithelium	UBERON:0000397	92.00	gold quality
orbitofrontal cortex	UBERON:0004167	91.69	gold quality
parietal lobe	UBERON:0001872	91.57	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	91.10	gold quality
prefrontal cortex	UBERON:0000451	90.90	gold quality
gastrocnemius	UBERON:0001388	90.34	gold quality
muscle of leg	UBERON:0001383	90.07	gold quality
frontal cortex	UBERON:0001870	90.04	gold quality
paraflocculus	UBERON:0005351	89.99	gold quality
superior frontal gyrus	UBERON:0002661	89.84	gold quality
hindlimb stylopod muscle	UBERON:0004252	89.83	gold quality
lymph node	UBERON:0000029	89.75	gold quality
neocortex	UBERON:0001950	89.66	gold quality
embryo	UBERON:0000922	89.45	gold quality
frontal pole	UBERON:0002795	89.43	gold quality
tonsil	UBERON:0002372	89.38	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	89.38	gold quality
stromal cell of endometrium	CL:0002255	89.30	gold quality
cerebellum	UBERON:0002037	89.06	gold quality
cingulate cortex	UBERON:0003027	89.03	gold quality
cerebral cortex	UBERON:0000956	89.00	gold quality
anterior cingulate cortex	UBERON:0009835	88.95	gold quality
Brodmann (1909) area 9	UBERON:0013540	88.83	gold quality
cerebellar cortex	UBERON:0002129	88.75	gold quality
cerebellar hemisphere	UBERON:0002245	88.68	gold quality
pons	UBERON:0000988	88.55	gold quality
skeletal muscle organ	UBERON:0014892	88.46	gold quality
muscle organ	UBERON:0001630	88.45	gold quality
telencephalon	UBERON:0001893	88.32	gold quality
hypothalamus	UBERON:0001898	88.21	gold quality
vermiform appendix	UBERON:0001154	88.16	gold quality
tibialis anterior	UBERON:0001385	88.13	silver quality
superior vestibular nucleus	UBERON:0007227	88.11	gold quality
corpus callosum	UBERON:0002336	88.09	gold quality
brain	UBERON:0000955	88.00	gold quality
central nervous system	UBERON:0001017	87.93	gold quality
entorhinal cortex	UBERON:0002728	87.93	gold quality
right frontal lobe	UBERON:0002810	87.87	gold quality
forebrain	UBERON:0001890	87.86	gold quality
bone marrow cell	CL:0002092	87.84	gold quality
adult organism	UBERON:0007023	87.83	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	87.74	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	87.61	gold quality
temporal lobe	UBERON:0001871	87.55	gold quality
right hemisphere of cerebellum	UBERON:0014890	87.52	gold quality
cranial nerve II	UBERON:0000941	87.46	gold quality
islet of Langerhans	UBERON:0000006	87.43	gold quality
amygdala	UBERON:0001876	87.39	gold quality
cerebellar vermis	UBERON:0004720	87.38	gold quality
ventral tegmental area	UBERON:0002691	87.29	gold quality
monocyte	CL:0000576	87.26	gold quality
leukocyte	CL:0000738	87.11	gold quality
mononuclear cell	CL:0000842	87.04	gold quality
body of uterus	UBERON:0009853	86.93	gold quality
subthalamic nucleus	UBERON:0001906	86.87	gold quality
caecum	UBERON:0001153	86.82	gold quality
Ammon’s horn	UBERON:0001954	86.82	gold quality
nucleus accumbens	UBERON:0001882	86.78	gold quality
popliteal artery	UBERON:0002250	86.71	gold quality
tibial artery	UBERON:0007610	86.70	gold quality
smooth muscle tissue	UBERON:0001135	86.57	gold quality
biceps brachii	UBERON:0001507	86.56	gold quality
left ovary	UBERON:0002119	86.53	gold quality
deltoid	UBERON:0001476	86.49	silver quality
caudate nucleus	UBERON:0001873	86.49	gold quality
putamen	UBERON:0001874	86.47	gold quality
inferior vagus X ganglion	UBERON:0005363	86.36	gold quality
ovary	UBERON:0000992	86.30	gold quality
substantia nigra pars reticulata	UBERON:0001966	86.28	gold quality
muscle tissue	UBERON:0002385	86.28	gold quality
skeletal muscle tissue	UBERON:0001134	86.24	gold quality
granulocyte	CL:0000094	86.03	gold quality
dorsal plus ventral thalamus	UBERON:0001897	85.99	gold quality
midbrain	UBERON:0001891	85.97	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	85.97	gold quality
ectocervix	UBERON:0012249	85.93	gold quality
aorta	UBERON:0000947	85.86	gold quality
lower esophagus mucosa	UBERON:0035834	85.85	gold quality
testis	UBERON:0000473	85.80	gold quality
substantia nigra	UBERON:0002038	85.80	gold quality
spinal cord	UBERON:0002240	85.79	gold quality
middle frontal gyrus	UBERON:0002702	85.79	gold quality
blood	UBERON:0000178	85.78	gold quality
endocervix	UBERON:0000458	85.76	gold quality
rectum	UBERON:0001052	85.75	gold quality
substantia nigra pars compacta	UBERON:0001965	85.75	gold quality
medulla oblongata	UBERON:0001896	85.69	gold quality
mucosa of transverse colon	UBERON:0004991	85.66	gold quality
myometrium	UBERON:0001296	85.64	gold quality
Brodmann (1909) area 10	UBERON:0013541	85.63	gold quality
cartilage tissue	UBERON:0002418	85.60	gold quality
pancreas	UBERON:0001264	85.54	gold quality
right ovary	UBERON:0002118	85.52	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	85.49	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.71

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Postcentral gyrus	tissue	61.7
Cerebellum	tissue	55.7	medium
Pons	tissue	51.2
Putamen	tissue	50.9
Thalamus	tissue	50.8
Midbrain	tissue	50.0
Hippocampal formation	tissue	49.1
Superior colliculi	tissue	49.0
Hypothalamus	tissue	48.7
Prefrontal cortex	tissue	48.5
Cerebral cortex	tissue	48.5	medium
Substantia nigra	tissue	48.4
Occipital cortex	tissue	47.8
Corpus callosum	tissue	47.1
Somatosensory cortex	tissue	46.8
Basal ganglia	tissue	46.3	medium
Motor cortex	tissue	46.0
Hippocampus	tissue	45.7	medium
Nucleus accumbens	tissue	45.6
Periaqueductal gray	tissue	45.6
Ventral forebrain	tissue	45.1
Medulla oblongata	tissue	44.9
Septum	tissue	44.6
Spinal cord	tissue	42.7
Retrosplenial and cingulate cortex	tissue	42.6
Entorhinal cortex	tissue	42.5
Locus coeruleus	tissue	42.1
Retrosplenial cortex	tissue	42.0
Tonsil	tissue	41.8	high
Olfactory bulb	tissue	40.8
Temporal cortex	tissue	39.5
Amygdala	tissue	37.3
Insular cortex	tissue	37.3
Lymph node	tissue	33.2	high
Choroid plexus	tissue	27.3
Frontal cortex	tissue	23.6
Skeletal muscle	tissue	23.2	medium
Caudate putamen	tissue	22.4
Tongue	tissue	20.6
Thymus	tissue	19.6
Retina	tissue	19.4
Smooth muscle	tissue	17.9	low
Bone marrow	tissue	17.4	low
Parathyroid gland	tissue	17.1	low
Endometrium 1	tissue	16.4	medium
Ovary	tissue	16.3	medium
Appendix	tissue	16.2	high
Pancreas	tissue	15.8	medium
Thyroid gland	tissue	15.6	medium
Testis	tissue	15.3	high
Placenta	tissue	15.1	medium
Spleen	tissue	14.9	medium
Colon	tissue	14.5	medium
Urinary bladder	tissue	14.5	medium
Fallopian tube	tissue	14.5	high
Epididymis	tissue	14.2	medium
Heart muscle	tissue	14.1	low
Esophagus	tissue	14.1	medium
Liver	tissue	13.7	low
Rectum	tissue	13.6	medium

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Orbitofrontal gyrus, anterior (65.1), Precentral gyrus (60.9), Postcentral gyrus, middle (60.3), Parietal operculum (58.5), Paracentral lobule, anterior (57.9).

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets:

Target	Regulation
ICAM1	Repression
NOS3	Activation

Upstream regulators (CollecTRI, top): REST, SP1

miRNA regulators (miRDB)

Targeting TERF2 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 68 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-1229-3P	99.97	66.49	906
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-4503	99.85	71.45	1869
HSA-MIR-4766-5P	99.75	69.23	2662
HSA-MIR-2681-5P	99.75	67.64	1655
HSA-MIR-7856-5P	99.75	69.99	2901
HSA-MIR-6745	99.74	65.33	1321
HSA-MIR-187-5P	99.74	70.26	1404
HSA-MIR-4428	99.73	66.41	1733
HSA-MIR-4719	99.73	72.10	3329
HSA-MIR-1825	99.72	68.11	1089
HSA-MIR-4530	99.69	66.47	1509
HSA-MIR-5093	99.67	69.26	2291
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-10393-5P	99.65	68.01	1368
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-497-3P	99.61	69.71	1990
HSA-MIR-4452	99.50	68.45	1493
HSA-MIR-4489	99.50	65.56	785
HSA-MIR-5584-5P	99.49	68.22	2814
HSA-MIR-4696	99.48	67.48	1040

Functional genomics

gnomAD constraint: pLI 0.999, LOEUF 0.444, missense Z 1.67 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000254942 splits into 6 regions with different missense tolerance; 1 is missense-constrained (≈2% of the expected missense variation). Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
16:69,356,901–69,357,530	33 / 69.9	0.47	no
16:69,357,531–69,368,446	211 / 236.8	0.89	no
16:69,368,447–69,384,704	97 / 157.0	0.62	no
16:69,384,705–69,385,428	1 / 17.3	0.06	yes (p 9.1e-05)
16:69,385,429–69,385,866	120 / 172.4	0.70	no
16:69,385,867–69,385,971	85 / 59.5	1.43	no
DepMap (CRISPR cell-line fitness): dependent in 96.5% of screened cell lines, common-essential.

Most-dependent cell lines (DepMap gene-effect, lower = stronger; ≤ −0.5 shown): SNU-668 (-1.745), Malme-3M (-1.712), Du4475 (-1.689), KASUMI-1 (-1.667), NCI-H522 (-1.575), NCO2 (-1.564), MEL-HO (-1.553), RPMI-7951 (-1.537), SCC-4 (-1.52), Caki-1 (-1.508), RKN (-1.508), CAS-1 (-1.497), COR-L105 (-1.491), SNU-182 (-1.48), KP-N-SI9s (-1.477).

Literature-anchored findings (GeneRIF, showing 40)

• TRF2-mediated end-capping occurs after telomere replication. (PMID:11577237)
• overexpression of TRF2 increased the rate of telomere shortening in primary cells without accelerating senescence (PMID:11923537)
• Co-localises with the interstitial TTAGGG repeats in interstitial telomeres. (PMID:11938440)
• Results showed that targeting of TRF1 and TRF2 to specific telomeres could be induced, and that targeting leads to telomere shortening. This indicates that these proteins act in cis to repress telomere elongation. (PMID:11971978)
• suggestion that TRF2 functions with WRN, and possibly BLM, in a common pathway at telomeric ends (PMID:12181313)
• Down-regulation of TRF1, TRF2 and TIN2 genes is important to maintain telomeric DNA for gastric cancers. (PMID:12530079)
• upregulation of TRF2 may contribute to telomere maintenance in malignant lymphoma (PMID:12915884)
• data show that the telosome reacts after DNA damage by upregulating telomerase activity and TRF2 expression in malignant cells (PMID:14513051)
• TRF2 is a component of neuroglial cells and appears to be involved in the cytoplasmic process formation that is necessary for neural differentiation. (PMID:14741354)
• PARP-2 physically binds to TRF2 with high affinity (PMID:14749375)
• Atomic force microscopy visualization of DNA end-loop formation by TRF2. (PMID:15005708)
• the nucleolus may sequester TRF2 and thereby influences its telomeric functions (PMID:15265990)
• TIN2 mutants defective in binding of TRF1 or TRF2 induce a DNA damage response and destabilize TRF1 and TRF2 at telomeres in human cells. (PMID:15292264)
• TRF2 binds the ATM kinase and can inhibit the ATM-dependent DNA damage response (PMID:15314656)
• TIN2 binds TRF1 and TRF2 simultaneously and stabilizes the TRF2 complex on telomeres (PMID:15316005)
• The enhancement of endothelial progenitor cell migratory activity by statins depends on TRF2 expression. (PMID:15520325)
• X-ray crystal structures of both TRF1- and TRF2-DNA binding domains in complex with telomeric DNA (2.0 and 1.8 angstroms resolution, respectively) show that they recognize the same TAGGGTT binding site by means of homeodomains (PMID:15608617)
• May be involved in multistep hepatocarcinogenesis by playing crucial role in telomere shortening. (PMID:15632001)
• Our results implicate TRF2 in an initial stage of DSB recognition and processing that occurs before association of ATM with DSBs and activation of the ATM-dependent DSB response network. (PMID:15665826)
• TRF2 may have a role in promoting tumorigenesis by accumulating and contributing to the cells’ ability to maintain an indefinite lifespan (PMID:15735711)
• Linking the induction of TRF2 phosphorylation to the DNA damage-response system, providing an example of direct cross-talk via a signaling pathway between these two major cellular processes. (PMID:16223874)
• Expression of TIN2, a gene regulator is increased in TIN2 expression in adult T-cell leukemia. (PMID:16786598)
• coordinated interactions among TPP1, TIN2, TRF1, and TRF2 may ensure robust assembly of the telosome, telomere targeting of its subunits, and, ultimately, regulated telomere maintenance (PMID:16880378)
• TRF2 binds to model replication forks and four-way junctions in vitro in a structure-specific but sequence-independent manner. (PMID:17052985)
• unanticipated nuclease-independent function of XPF in TRF2-mediated telomere shortening (PMID:17055345)
• Overexpression reduces telomeric, but not genomic, single strand break repair. (PMID:17395247)
• Biochemical fractionation and reconstitution revealed that telomere protection is mediated by a RAP1/TRF2 complex, providing evidence for direct role for human RAP1 in protection of telomeric DNA from nonhomologous end-joining at telomeric DNA ends. (PMID:17499040)
• TRF2 plays an essential role in homologous recombination by facilitating the formation of early recombination intermediates. (PMID:17670947)
• our hypothesis is that when the TRF length becomes shorter during tumour progression, the tumour cells can sustain a better tolerance to shorter telomere with the help of both TRF1 and TRF2, but without immediate activation of the telomerase (PMID:17681636)
• TRF2 is critical for the protection of A549 cells from both telomere erosion and DNA double-strand breaks driven by salvicine. (PMID:18025071)
• In alternative lengthening of telomere cells, TRF2 inactivation/silencing triggers cellular senescence and substantial loss of telomeric DNA upon stable TRF2 knockdown. (PMID:18056407)
• TRF1 and TRF2 bind to the dsDNA of telomeres, whereas POT1 binds to the ssDNA portion (PMID:18178559)
• localized the changes in deuterium uptake of hTRF2 as a function of varying amounts of a model oligodeoxynucleotide (PMID:18197706)
• results indicate that binding to the TRFH docking site involves the sequence F/Y-X-L-X-P in shelterin-associated proteins, which contacts the same molecular recognition surface of the TRFH domains of TRF1 & TRF2 with distinct specificities (PMID:18202258)
• Overexpression of TRF2B induces a p53-dependent DNA damage response in normal but not Werner syndrome fibroblasts. TRF2(DeltaB)-induced telomeric-loop homologous-recombination pathway requires WRN helicase. (PMID:18212065)
• Aurora C phosphorylates TRF2 (PMID:18309533)
• Increased TRF2 expression levels are found in T-cell leukemia cell lines and AML patients with poor prognosis. (PMID:18422278)
• we show that endogenous hSNM1B forms foci which colocalize at telomeres with TRF1 and TRF2 (PMID:18468965)
• The protein hSnm1B is stabilized when bound to the telomere-binding protein TRF2 (PMID:18593705)
• In normal B cells, transcriptional mechanisms exert a critical control over TfR1 and TfR2 expression, whereas in CLL post-transcriptional mechanisms seem to play a complementary and perhaps more important role (PMID:18621559)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	terfa	ENSDARG00000039302
mus_musculus	Terf2	ENSMUSG00000031921
rattus_norvegicus	Terf2	ENSRNOG00000020435

Paralogs (1): TERF1 (ENSG00000147601)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1195972) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 33 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal hepatocyte morphology	1
sebaceous gland atrophy	1
skin photosensitivity	1
increased sensitivity to skin irradiation	1
skin hyperplasia	1
epidermal atrophy	1
epidermal hyperplasia	1
abnormal skin morphology	1
hair follicle degeneration	1
abnormal keratinocyte physiology	1
abnormal chromosome morphology	1
premature aging	1
dry skin	1
induced chromosome breakage	1
increased incidence of tumors by UV-induction	1
increased cellular sensitivity to alkylating agent induced cell death	1
increased cellular sensitivity to ultraviolet irradiation induced cell death	1
chromosomal instability	1
abnormal epidermal pigmentation	1
decreased keratinocyte proliferation	1
increased skin squamous cell carcinoma incidence	1
focal dorsal hair loss	1
abnormal telomere morphology	1
increased skin tumor incidence	1
embryonic lethality, complete penetrance	1

+8 more (showing top 25).

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
Cricetulus griseus	O55036	97.7%	Diamond
Zea mays	B4FT40	89.6%	Diamond
Arabidopsis thaliana	Q9FJW5	65.3%	Diamond
Gallus gallus	Q9PU53	41.8%	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
MIR1538	ncRNA	100302119
TMED6	protein-coding	146456
CYB5B	protein-coding	80777
NFAT5	protein-coding	10725
NIP7	protein-coding	51388
VPS4A	protein-coding	27183
PDF	protein-coding	64146
SNTB2	protein-coding	6645
COG8	protein-coding	84342

Protein

Protein identifiers

Telomeric repeat-binding factor 2 — Q15554 (reviewed: Q15554)

Alternative names: TTAGGG repeat-binding factor 2, Telomeric DNA-binding protein

All UniProt accessions (9): H3BR06, H3BR37, H3BTA7, J3KSJ9, J3KSZ6, J3KTN8, Q15554, U3KQ35, V9GYM1

UniProt curated annotations — full annotation on UniProt →

Function. Binds the telomeric double-stranded 5’-TTAGGG-3’ repeat and plays a central role in telomere maintenance and protection against end-to-end fusion of chromosomes. In addition to its telomeric DNA-binding role, required to recruit a number of factors and enzymes required for telomere protection, including the shelterin complex, TERF2IP/RAP1 and DCLRE1B/Apollo. Component of the shelterin complex (telosome) that is involved in the regulation of telomere length and protection. Shelterin associates with arrays of double-stranded 5’-TTAGGG-3’ repeats added by telomerase and protects chromosome ends; without its protective activity, telomeres are no longer hidden from the DNA damage surveillance and chromosome ends are inappropriately processed by DNA repair pathways. Together with DCLRE1B/Apollo, plays a key role in telomeric loop (T loop) formation by generating 3’ single-stranded overhang at the leading end telomeres: T loops have been proposed to protect chromosome ends from degradation and repair. Required both to recruit DCLRE1B/Apollo to telomeres and activate the exonuclease activity of DCLRE1B/Apollo. Preferentially binds to positive supercoiled DNA. Together with DCLRE1B/Apollo, required to control the amount of DNA topoisomerase (TOP1, TOP2A and TOP2B) needed for telomere replication during fork passage and prevent aberrant telomere topology. Recruits TERF2IP/RAP1 to telomeres, thereby participating in to repressing homology-directed repair (HDR), which can affect telomere length.

Subunit / interactions. Homodimer. Component of the shelterin complex (telosome) composed of TERF1, TERF2, TINF2, TERF2IP/RAP1, ACD and POT1. Interacts with NBN; interaction takes place with unphosphorylated NBN during G1 phase and prevents to prevent ATM activation and non-homologous end joining repair. Interacts with SLX4/BTBD12. Interacts with DCLRE1B/Apollo and TERF2IP/RAP1; the interaction is direct. Interacts with DSP in the nucleus; the interaction is required for DSP telomere binding.

Subcellular location. Nucleus. Chromosome. Telomere.

Tissue specificity. Ubiquitous. Highly expressed in spleen, thymus, prostate, uterus, testis, small intestine, colon and peripheral blood leukocytes.

Post-translational modifications. Phosphorylated upon DNA damage, most probably by ATM. Phosphorylated TERF2 is not bound to telomeric DNA, and rapidly localizes to damage sites. Methylated by PRMT1 at multiple arginines within the N-terminal Arg-rich region. Methylation may control association with telomeres.

Domain organisation. The TRFH dimerization region mediates the interaction with DCLRE1B/Apollo but not TINF2. The HTH domain is an independent structural unit and mediates binding to telomeric DNA.

Isoforms (2)

UniProt ID	Names	Canonical?
Q15554-3	1	yes
Q15554-4	2

RefSeq proteins (1): NP_005643* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001005	SANT/Myb	Domain
IPR009057	Homeodomain-like_sf	Homologous_superfamily
IPR013867	Telomere_rpt-bd_fac_dimer_dom	Domain
IPR017357	TERF1/2	Family
IPR017930	Myb_dom	Domain
IPR030657	TERF2	Family
IPR031902	TERF2_RBM	Domain
IPR036507	Telomere_rpt-bd_fac_dimer_sf	Homologous_superfamily

Pfam: PF00249, PF08558, PF16772

UniProt features (51 total): helix 19, cross-link 6, turn 5, compositionally biased region 4, modified residue 4, region of interest 4, splice variant 2, strand 2, chain 1, domain 1, DNA-binding region 1, sequence variant 1, short sequence motif 1

Structure

Experimental structures (PDB)

18 structures by resolution:

PDB	Title	Method	Resolution (Å)
3SJM	Crystal Structure Analysis of TRF2-Dbd-DNA complex	X-RAY DIFFRACTION	1.35
1W0U	hTRF2 DNA-binding domain in complex with telomeric DNA.	X-RAY DIFFRACTION	1.8
3K6G	Crystal structure of Rap1 and TRF2 complex	X-RAY DIFFRACTION	1.95
4M7C	Crystal structure of the TRF2-binding motif of SLX4 in complex with the TRFH domain of …	X-RAY DIFFRACTION	2.05
6J67	Crystal structure of the compound 34 in a complex with TRF2	X-RAY DIFFRACTION	2.05
3BU8	Crystal Structure of TRF2 TRFH domain and TIN2 peptide complex	X-RAY DIFFRACTION	2.15
7C5D	Crystal structure of TRF2 TRFH domain in complex with a MCPH1 peptide	X-RAY DIFFRACTION	2.15
1H6P	Dimeristion domain from human TRF2	X-RAY DIFFRACTION	2.2
5XYF	Crystal structure of the human TIN2-TPP1-TRF2 telomeric complex	X-RAY DIFFRACTION	2.2
4RQI	Structure of TRF2/RAP1 secondary interaction binding site	X-RAY DIFFRACTION	2.44
3BUA	Crystal Structure of TRF2 TRFH domain and APOLLO peptide complex	X-RAY DIFFRACTION	2.5
9Q9K	Cryo-EM structure of human Mre11-Rad50 (MR) complex bound to DNA and telomeric factor …	ELECTRON MICROSCOPY	2.59
9Q9J	Cryo-EM structure of human Mre11-Rad50-Nbs1 (MRN) complex bound to DNA and telomeric …	ELECTRON MICROSCOPY	2.71
9Q9M	Cryo-EM structure of human Mre11-Rad50-Nbs1 (MRN) complex bound to DNA and telomeric …	ELECTRON MICROSCOPY	2.81
5WQD	Crystal structure of TRF2 TRFH in complex with an NBS1 peptide	X-RAY DIFFRACTION	3
1VF9	Solution Structure Of Human Trf2	SOLUTION NMR
1VFC	Solution Structure Of The DNA Complex Of Human Trf2	SOLUTION NMR
1XG1	Solution structure of Myb-domain of human TRF2	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15554-F1	69.36	0.41

Human Protein Atlas

Protein class: Predicted intracellular proteins, Essential proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): nuclear bodies; nucleoplasm

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 (10)

Type	Positions
Asymmetric dimethylarginine	59
Omega-n-methylarginine	60
Phosphothreonine	230
Phosphoserine	365
Glycyl lysine isopeptide (lys-gly) (interchain with g-cter in sumo2)	287, 335, 353, 369, 375, 452

Function

Pathways and Gene Ontology

Reactome pathways

9 curated (TAS) of 28; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

28 pathways:

ID	Pathway	Evidence
R-HSA-2559586	DNA Damage/Telomere Stress Induced Senescence	curated
R-HSA-9670095	Inhibition of DNA recombination at telomere	curated
R-HSA-171306	Packaging Of Telomere Ends	curated
R-HSA-174411	Polymerase switching on the C-strand of the telomere	curated
R-HSA-174414	Processive synthesis on the C-strand of the telomere	curated
R-HSA-174437	Removal of the Flap Intermediate from the C-strand	curated
R-HSA-174417	Telomere C-strand (Lagging Strand) Synthesis	curated
R-HSA-174430	Telomere C-strand synthesis initiation	curated
R-HSA-171319	Telomere Extension By Telomerase	curated
R-HSA-73884	Base Excision Repair	—
R-HSA-73929	Base-Excision Repair, AP Site Formation	—
R-HSA-1640170	Cell Cycle	—
R-HSA-2559583	Cellular Senescence	—
R-HSA-8953897	Cellular responses to stimuli	—
R-HSA-2262752	Cellular responses to stress	—
R-HSA-73886	Chromosome Maintenance	—
R-HSA-110331	Cleavage of the damaged purine	electronic
R-HSA-110329	Cleavage of the damaged pyrimidine	electronic
R-HSA-73894	DNA Repair	—
R-HSA-73927	Depurination	—
R-HSA-73928	Depyrimidination	—
R-HSA-180786	Extension of Telomeres	—
R-HSA-1500620	Meiosis	—
R-HSA-1221632	Meiotic synapsis	electronic
R-HSA-110330	Recognition and association of DNA glycosylase with site containing an affected purine	electronic
R-HSA-110328	Recognition and association of DNA glycosylase with site containing an affected pyrimidine	electronic
R-HSA-1474165	Reproduction	—
R-HSA-157579	Telomere Maintenance	—

MSigDB gene sets: 254 (showing top): GOBP_RNA_TEMPLATED_DNA_BIOSYNTHETIC_PROCESS, GOBP_CHROMOSOME_ORGANIZATION, GOBP_REGULATION_OF_DNA_RECOMBINATION, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_AXO_DENDRITIC_TRANSPORT, GOBP_NEGATIVE_REGULATION_OF_TELOMERE_MAINTENANCE_VIA_TELOMERASE, chr16q22, PID_TELOMERASE_PATHWAY, GOBP_TELOMERE_CAPPING, REACTOME_MEIOTIC_SYNAPSIS, GOBP_CELL_CYCLE_DNA_REPLICATION, GOBP_NEGATIVE_REGULATION_OF_DNA_REPAIR, GOBP_NEGATIVE_REGULATION_OF_DNA_RECOMBINATION, DACOSTA_UV_RESPONSE_VIA_ERCC3_UP, GOBP_TELOMERE_MAINTENANCE_VIA_TELOMERE_LENGTHENING

GO Biological Process (23): telomere maintenance (GO:0000723), RNA-templated DNA biosynthetic process (GO:0006278), telomere capping (GO:0016233), telomeric loop formation (GO:0031627), protection from non-homologous end joining at telomere (GO:0031848), regulation of telomere maintenance (GO:0032204), negative regulation of telomere maintenance (GO:0032205), positive regulation of telomere maintenance (GO:0032206), negative regulation of telomere maintenance via recombination (GO:0032208), regulation of telomere maintenance via telomerase (GO:0032210), negative regulation of telomere maintenance via telomerase (GO:0032211), negative regulation of telomere maintenance via semi-conservative replication (GO:0032214), telomeric D-loop disassembly (GO:0061820), protein localization to chromosome, telomeric region (GO:0070198), cellular senescence (GO:0090398), axonal transport of messenger ribonucleoprotein complex (GO:0099088), negative regulation of telomere single strand break repair (GO:1903824), negative regulation of telomere capping (GO:1904354), negative regulation of telomere maintenance via telomere lengthening (GO:1904357), negative regulation of t-circle formation (GO:1904430), negative regulation of telomeric D-loop disassembly (GO:1905839), negative regulation of cellular senescence (GO:2000773), positive regulation of protein localization (GO:1903829)

GO Molecular Function (9): double-stranded telomeric DNA binding (GO:0003691), enzyme binding (GO:0019899), telomeric repeat DNA binding (GO:0042162), protein homodimerization activity (GO:0042803), protein-containing complex binding (GO:0044877), G-rich strand telomeric DNA binding (GO:0098505), DNA binding (GO:0003677), telomerase activity (GO:0003720), protein binding (GO:0005515)

GO Cellular Component (9): chromosome, telomeric region (GO:0000781), nuclear telomere cap complex (GO:0000783), male germ cell nucleus (GO:0001673), nucleus (GO:0005634), nucleoplasm (GO:0005654), nuclear body (GO:0016604), axon (GO:0030424), shelterin complex (GO:0070187), telomere cap complex (GO:0000782)

Reactome top-level categories

12 top-level categories:

Category	Pathways
Telomere Maintenance	3
Telomere C-strand (Lagging Strand) Synthesis	3
Depyrimidination	2
Depurination	2
Extension of Telomeres	2
Meiosis	1
Processive synthesis on the C-strand of the telomere	1
Cellular Senescence	1
Reproduction	1
Cell Cycle	1
Chromosome Maintenance	1
Cellular responses to stimuli	1

GO top-level categories

showing 60 of 62 GO namespaces:

Category	Terms
telomere maintenance	5
negative regulation of telomere maintenance	4
telomere capping	2
regulation of telomere maintenance	2
negative regulation of DNA metabolic process	2
telomere maintenance via telomerase	2
regulation of telomere maintenance via telomere lengthening	2
binding	2
DNA metabolic process	1
telomere organization	1
DNA biosynthetic process	1
telomere maintenance in response to DNA damage	1
regulation of chromosome organization	1
regulation of DNA metabolic process	1
negative regulation of chromosome organization	1
positive regulation of DNA metabolic process	1
positive regulation of chromosome organization	1
telomere maintenance via recombination	1
regulation of telomere maintenance via recombination	1
negative regulation of mitotic recombination	1
negative regulation of DNA recombination at telomere	1
regulation of DNA biosynthetic process	1
regulation of telomere maintenance via telomerase	1
negative regulation of telomere maintenance via telomere lengthening	1
negative regulation of DNA biosynthetic process	1
negative regulation of cell cycle process	1
telomere maintenance via semi-conservative replication	1
regulation of telomere maintenance via semi-conservative replication	1
telomeric loop disassembly	1
protein localization to chromosome	1
cellular process	1
cellular response to stress	1
axonal transport	1
negative regulation of single strand break repair	1
telomere single strand break repair	1
regulation of telomere capping	1
telomere maintenance via telomere lengthening	1
negative regulation of cellular component organization	1
t-circle formation	1
regulation of t-circle formation	1
double-stranded DNA binding	1
telomeric repeat DNA binding	1
protein binding	1
sequence-specific DNA binding	1
identical protein binding	1
protein dimerization activity	1
single-stranded telomeric DNA binding	1
nucleic acid binding	1
RNA-directed DNA polymerase activity	1
chromosomal region	1
telomere cap complex	1
nuclear protein-containing complex	1
germ cell nucleus	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cellular anatomical structure	1
nucleoplasm	1
intracellular membraneless organelle	1
neuron projection	1
nuclear telomere cap complex	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 29 of 41 annotations. The rest are phylogenetic / computational / electronic (IEA).

29 experimentally-supported GO terms:

GO term	NS	Evidence
negative regulation of cellular senescence	BP	mutant phenotype
negative regulation of t-circle formation	BP	mutant phenotype
negative regulation of telomere capping	BP	mutant phenotype
negative regulation of telomere maintenance	BP	mutant phenotype
negative regulation of telomere maintenance via recombination	BP	mutant phenotype
negative regulation of telomere maintenance via telomerase	BP	direct assay
negative regulation of telomere maintenance via telomere lengthening	BP	mutant phenotype
negative regulation of telomeric D-loop disassembly	BP	direct assay
positive regulation of telomere maintenance	BP	direct assay
protection from non-homologous end joining at telomere	BP	mutant phenotype
protein localization to chromosome, telomeric region	BP	mutant phenotype
regulation of telomere maintenance	BP	mutant phenotype
regulation of telomere maintenance via telomerase	BP	direct assay
telomere capping	BP	direct assay
telomere maintenance	BP	direct assay
telomeric D-loop disassembly	BP	genetic interaction
telomeric loop formation	BP	direct assay
chromosome, telomeric region	CC	direct assay
nuclear body	CC	direct assay
nuclear telomere cap complex	CC	direct assay
nucleoplasm	CC	direct assay
nucleus	CC	direct assay
shelterin complex	CC	direct assay
G-rich strand telomeric DNA binding	MF	direct assay
double-stranded telomeric DNA binding	MF	direct assay
enzyme binding	MF	physical interaction
protein homodimerization activity	MF	physical interaction
protein-containing complex binding	MF	physical interaction
telomeric repeat DNA binding	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 1,490 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TERF2	TINF2	Q9BSI4	942
TERF2	TERF2IP	Q9NYB0	941
TERF2	ACD	Q96AP0	899
TERF2	POT1	Q9NUX5	879
TERF2	DCLRE1B	Q9H816	854
TERF2	TNKS	O95271	752
TERF2	ATM	Q13315	737
TERF2	MUS81	Q96NY9	736
TERF2	EME1	Q96AY2	713
TERF2	SLX4	Q8IY92	712
TERF2	WRN	Q14191	701
TERF2	RAD50	Q92878	679
TERF2	SLX4IP	Q5VYV7	674
TERF2	TERT	O14746	648
TERF2	TERF1	P54274	647

IntAct

Human interaction partners of TERF2 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

showing 30 of 67 partners by confidence:

Partner	Interaction type	MIscore	Records
TERF2IP	physical association	0.970	27
DCLRE1B	physical association	0.920	9
TINF2	association	0.890	9
POT1	association	0.890	7
ACD	association	0.810	5
BLM	direct interaction	0.690	8
H2AX	physical association	0.680	4
WRN	physical association	0.660	8
SLX4	association	0.660	2
ORC2	physical association	0.600	3
MCPH1	association	0.580	5
DDX39A	physical association	0.550	1
XRCC6	physical association	0.550	1
ATM	physical association	0.540	2
ORC1	physical association	0.540	2
EBNA1	physical association	0.520	3
CCDC137	physical association	0.510	2
DDX21	physical association	0.510	2
HDGFL2	physical association	0.510	2
HEXIM1	physical association	0.510	2
HMGN2	physical association	0.510	2
NAIF1	physical association	0.510	2
RPL13	physical association	0.510	2
ZC3H18	physical association	0.510	2
TOP3A	colocalization	0.460	4
TP53BP1	colocalization	0.450	1
H2BC9	physical association	0.400	1
PIAS1	physical association	0.400	1
AFAP1L2	physical association	0.370	1
ANXA5	physical association	0.370	1

BioGRID (526 interactions; top human partners by supporting records): TERF2IP (Affinity Capture-Western; 34 records), TINF2 (Affinity Capture-Western; 18 records), SLX4 (Affinity Capture-Western; 15 records), DCLRE1B (Affinity Capture-MS; 10 records), POT1 (Affinity Capture-MS; 9 records), BRCA1 (Affinity Capture-MS; 6 records), NBN (Affinity Capture-Western; 6 records), WRN (Affinity Capture-Western; 6 records), MRE11A (Affinity Capture-Western; 5 records), RAD50 (Affinity Capture-Western; 5 records), XRCC6 (Affinity Capture-MS; 5 records), BLM (Reconstituted Complex; 4 records), EP300 (Affinity Capture-Western; 4 records), HIST2H2AC (Affinity Capture-Western; 4 records), PIAS1 (Affinity Capture-Western; 4 records)

SIGNOR signaling

5 signaling interactions:

A	Effect	B	Mechanism
TERF2	“form complex”	“Shelterin complex”	binding
TERF2	down-regulates	Neurogenesis
HNRNPH2	“down-regulates quantity”	TERF2	“post transcriptional regulation”
HNRNPH1	“down-regulates quantity”	TERF2	“post transcriptional regulation”
TERF2	“down-regulates activity”	ATM	binding

Protein complexes (CORUM) (14)

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

14 complexes by size:

Complex	Subunits	Members
MCPH1-Condensin II complex	8	NCAPD3, NCAPG2, NCAPH2, SMC2, SMC4, TERF2, TERF2IP, MCPH1
★ Rap1 complex	7	RAD50, TERF2, TERF2IP, XRCC5, XRCC6, MRE11, PARP1
Rap1 complex	7	RAD50, TERF1, TERF2, TERF2IP, TINF2, ACD, POT1
TERF2-RAP1 complex	7	MRE11, RAD50, TERF2, TERF2IP, TINF2, XRCC5, XRCC6
TRF-Rap1 complex I, 2MD	6	TERF2, TERF2IP, TINF2, TNKS, POT1, TERF1
Telomere-associated protein complex	6	ACD, POT1, TERF1, TERF2, TERF2IP, TINF2
TIN2 complex	4	TINF2, ACD, POT1, TERF2
TRF2-Rap1 complex II	4	TINF2, POT1, TERF2, TERF2IP
MRE11A-RAD50-NBN-TRF2 complex	4	MRE11, NBN, RAD50, TERF2
TRF2-Ku complex	3	XRCC5, XRCC6, TERF2
TFIIA-TRF2 complex	3	GTF2A1, GTF2A2, TERF2
TRF2-Rap1 complex III	2	TERF2IP, TERF2
WRN-TRF2 complex	2	WRN, TERF2
BLM-TRF2 complex	2	BLM, TERF2

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 67 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
Processive synthesis on the C-strand of the telomere	6	99.3×	2e-09
Telomere C-strand (Lagging Strand) Synthesis	6	99.3×	2e-09
Removal of the Flap Intermediate from the C-strand	6	82.8×	6e-09
Extension of Telomeres	5	65.3×	3e-07
Telomere Extension By Telomerase	5	49.6×	1e-06
Impaired BRCA2 binding to PALB2	5	49.6×	1e-06
Polymerase switching on the C-strand of the telomere	5	46.0×	1e-06
Defective homologous recombination repair (HRR) due to BRCA1 loss of function	5	46.0×	1e-06

GO biological processes:

GO term	Partners	Fold	FDR
telomere maintenance	12	51.0×	3e-15
positive regulation of telomere maintenance	6	48.6×	4e-07
double-strand break repair via nonhomologous end joining	5	33.4×	2e-05
DNA recombination	5	26.8×	5e-05
double-strand break repair via homologous recombination	8	19.8×	6e-07
double-strand break repair	6	19.3×	3e-05
DNA replication	6	15.7×	7e-05
chromatin organization	6	9.4×	8e-04

Disease & clinical

Genetic variants

Variant evidence for TERF2: 68 ClinVar records (0 pathogenic / likely pathogenic); 6 GWAS associations.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	27
Likely benign	17
Benign	14

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 32 predictions of 902):

Position(s)	Effect	Δscore	Sites
16:69368505	acceptor_gain	1.0000
16:69385390	donor_loss	1.0000	2
16:69385592	donor_loss	1.0000
16:69357562–69357563	acceptor_loss	0.9900	4
16:69367200–69367201	acceptor_loss	0.9900	6
16:69368374–69368375	donor_loss	0.9900	5
16:69368483–69368484	acceptor_loss	0.9900	6
16:69370481–69370482	donor_loss	0.9900	5
16:69370644	acceptor_gain	0.9900
16:69370656	acceptor_gain	0.9900

AlphaMissense

1,188 missense substitutions predicted likely pathogenic (of 3,525 scored), across 271 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
M528	9	0.960	0.994
M146	9	0.920	0.999
M536	9	0.884	0.991
M263	9	0.882	0.997
M125	9	0.865	0.995
D531	8	0.998	0.999
F162	8	0.995	1.000
D123	8	0.992	0.997
F118	8	0.988	1.000
F521	8	0.987	0.999
D163	8	0.981	0.995
F259	8	0.972	0.998
F254	8	0.958	0.998
F110	8	0.947	0.999
N95	8	0.936	0.997
F185	8	0.928	0.994
H248	8	0.927	0.995
D117	8	0.915	0.967
F347	8	0.915	0.987
D159	8	0.912	0.975

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
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	0.000308
Kidney Renal Clear Cell Carcinoma (validation)	favorable	0.000799

Disease associations

OMIM: gene MIM:602027 | disease phenotypes:

GWAS associations

6 associations:

Study	Trait	p-value
GCST011494_16	Daytime nap	1e-12
GCST005951_23	Body mass index	5e-11
GCST010703_36	Brain morphology (MOSTest)	5e-11
GCST009856_43	Leukocyte telomere length	5e-10
GCST007269_136	Pulse pressure	3e-9
GCST007006_16	Logical memory (delayed recall) in normal cognition	7e-7

EFO canonical traits (from GWAS)

5 canonical traits:

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0004874	memory performance
EFO:0005763	pulse pressure measurement
EFO:0004346	neuroimaging measurement
EFO:0007828	daytime rest measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4296012 (SINGLE PROTEIN)

PharmGKB: 1 entry (CPIC guideline: no)

Binding affinities (BindingDB)

57 measured of 59 human assays (59 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CHEMBL4166000	KI	90 nM
CHEMBL4163499	KI	210 nM
CHEMBL4172926	KI	240 nM
CHEMBL4782698	KI	330 nM
CHEMBL4176290	KI	340 nM
CHEMBL4163072	KI	380 nM
CHEMBL4161391	KI	510 nM
CHEMBL4161856	KI	720 nM
CHEMBL4159482	KI	1400 nM
CHEMBL4160402	KI	1890 nM
CHEMBL4168423	KI	2200 nM
CHEMBL4745325	KD	2500 nM
CHEMBL4167227	KI	3200 nM
CHEMBL4169779	KI	3400 nM
CHEMBL4792503	KI	4300 nM
CHEMBL4168052	KI	4700 nM
CHEMBL4759024	KI	4900 nM
CHEMBL4746160	KI	5100 nM
CHEMBL4750127	KI	5200 nM
CHEMBL4166947	KI	6100 nM
CHEMBL4745167	KI	6900 nM
CHEMBL4165033	KI	8500 nM
CHEMBL4779157	KI	8800 nM
CHEMBL4744656	KI	11000 nM
CHEMBL4176438	KI	11200 nM
CHEMBL4174183	KI	11300 nM
CHEMBL4758244	KI	13000 nM
CHEMBL4754108	KI	13000 nM
CHEMBL4168576	KI	14000 nM
CHEMBL4755348	KI	14000 nM
CHEMBL4173933	KI	18400 nM
CHEMBL4798222	KI	20000 nM
CHEMBL4747023	KI	21000 nM
CHEMBL4175710	KI	22800 nM
CHEMBL4161034	KI	26300 nM
CHEMBL4175503	KI	26800 nM
CHEMBL4753207	KI	29000 nM
CHEMBL4756209	KI	30000 nM
CHEMBL4788808	KI	30000 nM
CHEMBL4743336	KI	32000 nM
CHEMBL4753987	KI	35000 nM
CHEMBL4762330	KI	39000 nM
CHEMBL4756877	KI	39000 nM
CHEMBL4782236	KI	39000 nM
CHEMBL4174968	KI	41400 nM
CHEMBL4159840	KI	43200 nM
CHEMBL4756780	KI	46000 nM
CHEMBL4170375	KI	58200 nM
CHEMBL4798800	KI	61000 nM
CHEMBL4175252	KI	61200 nM

ChEMBL bioactivities

25 potent at pChembl≥5 of 55 total, top 24 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.05	Ki	90	nM	CHEMBL4166000
6.68	Ki	210	nM	CHEMBL4163499
6.62	Ki	240	nM	CHEMBL4172926
6.48	Ki	330	nM	CHEMBL4782698
6.47	Ki	340	nM	CHEMBL4176290
6.42	Ki	380	nM	CHEMBL4163072
6.29	Ki	510	nM	CHEMBL4161391
6.14	Ki	720	nM	CHEMBL4161856
5.85	Ki	1400	nM	CHEMBL4159482
5.72	Ki	1890	nM	CHEMBL4160402
5.66	Ki	2200	nM	CHEMBL4168423
5.60	Kd	2500	nM	CHEMBL4745325
5.50	Ki	3200	nM	CHEMBL4167227
5.47	Ki	3400	nM	CHEMBL4169779
5.38	Ki	4200	nM	CHEMBL4745325
5.37	Ki	4300	nM	CHEMBL4792503
5.33	Ki	4700	nM	CHEMBL4168052
5.31	Ki	4900	nM	CHEMBL4759024
5.29	Ki	5100	nM	CHEMBL4746160
5.28	Ki	5200	nM	CHEMBL4750127
5.21	Ki	6100	nM	CHEMBL4166947
5.16	Ki	6900	nM	CHEMBL4745167
5.07	Ki	8500	nM	CHEMBL4165033
5.06	Ki	8800	nM	CHEMBL4779157

PubChem BioAssay actives

25 with measured affinity, of 64 total; 23 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
(3S,6S,9S,17S,20S)-9-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-acetamido-4-methylpentanoyl]amino]propanoyl]amino]-4-methylpentanoyl]amino]-6-aminohexanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-N,N,3-trimethyl-6-(2-methylpropyl)-2,5,8,19-tetraoxo-1,4,7,18-tetrazabicyclo[18.3.0]tricosane-17-carboxamide	1355116: Displacement of 5-((2R,6S,9S,12S,15S,18S,21S,24S)-3-((S)-2-((S)-1-amino-3-methyl-1-oxobutan-2-ylcarbamoyl)pyrrolidine-1-carbonyl)-15-(4-aminobutyl)-2-hydroxy-12-(4-hydroxybenzyl)-6,9,18,24-tetraisobutyl-21-methyl-5,8,11,14,17,20,23,26,29-nonaoxo-4,7,10,13,16,19,22,25,28-nonaazatetratriacontan-34-ylcarbamoyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid from TRF2 TRFH domain (unknown origin) after 30 mins by fluorescence polarization assay	ki	0.0900	uM
(2S)-1-[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-acetamido-4-methylpentanoyl]amino]propanoyl]amino]-4-methylpentanoyl]amino]-6-aminohexanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-methylpentanoyl]amino]-2-cyclohexylacetyl]amino]-3-hydroxybutanoyl]-N-[(2S)-1-amino-3-methyl-1-oxobutan-2-yl]pyrrolidine-2-carboxamide	1355116: Displacement of 5-((2R,6S,9S,12S,15S,18S,21S,24S)-3-((S)-2-((S)-1-amino-3-methyl-1-oxobutan-2-ylcarbamoyl)pyrrolidine-1-carbonyl)-15-(4-aminobutyl)-2-hydroxy-12-(4-hydroxybenzyl)-6,9,18,24-tetraisobutyl-21-methyl-5,8,11,14,17,20,23,26,29-nonaoxo-4,7,10,13,16,19,22,25,28-nonaazatetratriacontan-34-ylcarbamoyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid from TRF2 TRFH domain (unknown origin) after 30 mins by fluorescence polarization assay	ki	0.2100	uM
(2S)-1-[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-acetamido-4-methylpentanoyl]amino]propanoyl]amino]-4-methylpentanoyl]amino]-6-aminohexanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-methylpentanoyl]amino]-4-methylpentanoyl]amino]propanoyl]-N-[(2S)-1-amino-3-methyl-1-oxobutan-2-yl]pyrrolidine-2-carboxamide	1355116: Displacement of 5-((2R,6S,9S,12S,15S,18S,21S,24S)-3-((S)-2-((S)-1-amino-3-methyl-1-oxobutan-2-ylcarbamoyl)pyrrolidine-1-carbonyl)-15-(4-aminobutyl)-2-hydroxy-12-(4-hydroxybenzyl)-6,9,18,24-tetraisobutyl-21-methyl-5,8,11,14,17,20,23,26,29-nonaoxo-4,7,10,13,16,19,22,25,28-nonaazatetratriacontan-34-ylcarbamoyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid from TRF2 TRFH domain (unknown origin) after 30 mins by fluorescence polarization assay	ki	0.2400	uM
(2S)-1-[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-acetamido-4-methylpentanoyl]amino]propanoyl]amino]-4-methylpentanoyl]amino]-6-aminohexanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-methylpentanoyl]amino]-4-methylpentanoyl]amino]-3-hydroxybutanoyl]-N-[(2S)-1-amino-3-methyl-1-oxobutan-2-yl]pyrrolidine-2-carboxamide	1675871: Binding affinity to TRFH domain of TRF2 (residues 42 to 245) (unknown origin) by FP based assay	ki	0.3300	uM
(2S)-2-[[(2S)-1-[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-acetamido-4-methylpentanoyl]amino]propanoyl]amino]-4-methylpentanoyl]amino]-6-aminohexanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-methylpentanoyl]amino]-4-methylpentanoyl]amino]-3-hydroxybutanoyl]pyrrolidine-2-carbonyl]amino]-3-methylbutanoic acid	1355116: Displacement of 5-((2R,6S,9S,12S,15S,18S,21S,24S)-3-((S)-2-((S)-1-amino-3-methyl-1-oxobutan-2-ylcarbamoyl)pyrrolidine-1-carbonyl)-15-(4-aminobutyl)-2-hydroxy-12-(4-hydroxybenzyl)-6,9,18,24-tetraisobutyl-21-methyl-5,8,11,14,17,20,23,26,29-nonaoxo-4,7,10,13,16,19,22,25,28-nonaazatetratriacontan-34-ylcarbamoyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid from TRF2 TRFH domain (unknown origin) after 30 mins by fluorescence polarization assay	ki	0.3400	uM
(2S)-2-[[(2S)-1-[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[(2-aminoacetyl)amino]-4-methylpentanoyl]amino]propanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-methylpentanoyl]amino]-4-methylpentanoyl]amino]-3-hydroxybutanoyl]pyrrolidine-2-carbonyl]amino]-3-methylbutanoic acid	1355116: Displacement of 5-((2R,6S,9S,12S,15S,18S,21S,24S)-3-((S)-2-((S)-1-amino-3-methyl-1-oxobutan-2-ylcarbamoyl)pyrrolidine-1-carbonyl)-15-(4-aminobutyl)-2-hydroxy-12-(4-hydroxybenzyl)-6,9,18,24-tetraisobutyl-21-methyl-5,8,11,14,17,20,23,26,29-nonaoxo-4,7,10,13,16,19,22,25,28-nonaazatetratriacontan-34-ylcarbamoyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid from TRF2 TRFH domain (unknown origin) after 30 mins by fluorescence polarization assay	ki	0.3800	uM
(2S)-1-[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-acetamido-4-methylpentanoyl]amino]propanoyl]amino]-4-methylpentanoyl]amino]-6-aminohexanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-methylpentanoyl]amino]-2-cyclopentylacetyl]amino]-3-hydroxybutanoyl]-N-[(2S)-1-amino-3-methyl-1-oxobutan-2-yl]pyrrolidine-2-carboxamide	1355116: Displacement of 5-((2R,6S,9S,12S,15S,18S,21S,24S)-3-((S)-2-((S)-1-amino-3-methyl-1-oxobutan-2-ylcarbamoyl)pyrrolidine-1-carbonyl)-15-(4-aminobutyl)-2-hydroxy-12-(4-hydroxybenzyl)-6,9,18,24-tetraisobutyl-21-methyl-5,8,11,14,17,20,23,26,29-nonaoxo-4,7,10,13,16,19,22,25,28-nonaazatetratriacontan-34-ylcarbamoyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid from TRF2 TRFH domain (unknown origin) after 30 mins by fluorescence polarization assay	ki	0.5100	uM
(2S)-1-[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-acetamido-4-methylpentanoyl]amino]propanoyl]amino]-4-methylpentanoyl]amino]-6-aminohexanoyl]amino]-3-(4-aminophenyl)propanoyl]amino]-4-methylpentanoyl]amino]-4-methylpentanoyl]amino]-3-hydroxybutanoyl]-N-[(2S)-1-amino-3-methyl-1-oxobutan-2-yl]pyrrolidine-2-carboxamide	1355116: Displacement of 5-((2R,6S,9S,12S,15S,18S,21S,24S)-3-((S)-2-((S)-1-amino-3-methyl-1-oxobutan-2-ylcarbamoyl)pyrrolidine-1-carbonyl)-15-(4-aminobutyl)-2-hydroxy-12-(4-hydroxybenzyl)-6,9,18,24-tetraisobutyl-21-methyl-5,8,11,14,17,20,23,26,29-nonaoxo-4,7,10,13,16,19,22,25,28-nonaazatetratriacontan-34-ylcarbamoyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid from TRF2 TRFH domain (unknown origin) after 30 mins by fluorescence polarization assay	ki	0.7200	uM
(2S)-1-[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-acetamido-4-methylpentanoyl]amino]propanoyl]amino]-4-methylpentanoyl]amino]-6-aminohexanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-methylpentanoyl]amino]-3-cyclohexylpropanoyl]amino]-3-hydroxybutanoyl]-N-[(2S)-1-amino-3-methyl-1-oxobutan-2-yl]pyrrolidine-2-carboxamide	1355116: Displacement of 5-((2R,6S,9S,12S,15S,18S,21S,24S)-3-((S)-2-((S)-1-amino-3-methyl-1-oxobutan-2-ylcarbamoyl)pyrrolidine-1-carbonyl)-15-(4-aminobutyl)-2-hydroxy-12-(4-hydroxybenzyl)-6,9,18,24-tetraisobutyl-21-methyl-5,8,11,14,17,20,23,26,29-nonaoxo-4,7,10,13,16,19,22,25,28-nonaazatetratriacontan-34-ylcarbamoyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid from TRF2 TRFH domain (unknown origin) after 30 mins by fluorescence polarization assay	ki	1.4000	uM
(2S)-1-[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-acetamido-4-methylpentanoyl]amino]propanoyl]amino]-4-methylpentanoyl]amino]-6-aminohexanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-methylpentanoyl]amino]-4-methylpentanoyl]amino]-3-hydroxybutanoyl]pyrrolidine-2-carboxylic acid	1355116: Displacement of 5-((2R,6S,9S,12S,15S,18S,21S,24S)-3-((S)-2-((S)-1-amino-3-methyl-1-oxobutan-2-ylcarbamoyl)pyrrolidine-1-carbonyl)-15-(4-aminobutyl)-2-hydroxy-12-(4-hydroxybenzyl)-6,9,18,24-tetraisobutyl-21-methyl-5,8,11,14,17,20,23,26,29-nonaoxo-4,7,10,13,16,19,22,25,28-nonaazatetratriacontan-34-ylcarbamoyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid from TRF2 TRFH domain (unknown origin) after 30 mins by fluorescence polarization assay	ki	1.8900	uM
(2S)-2-[[(2S)-1-[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-4-methylpentanoyl]amino]propanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-methylpentanoyl]amino]-4-methylpentanoyl]amino]-3-hydroxybutanoyl]pyrrolidine-2-carbonyl]amino]-3-methylbutanoic acid	1355116: Displacement of 5-((2R,6S,9S,12S,15S,18S,21S,24S)-3-((S)-2-((S)-1-amino-3-methyl-1-oxobutan-2-ylcarbamoyl)pyrrolidine-1-carbonyl)-15-(4-aminobutyl)-2-hydroxy-12-(4-hydroxybenzyl)-6,9,18,24-tetraisobutyl-21-methyl-5,8,11,14,17,20,23,26,29-nonaoxo-4,7,10,13,16,19,22,25,28-nonaazatetratriacontan-34-ylcarbamoyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid from TRF2 TRFH domain (unknown origin) after 30 mins by fluorescence polarization assay	ki	2.2000	uM
(3S,6S,9S,18S,21S)-9-[[3-(cyclopropylmethoxy)-5-phenylmethoxybenzoyl]amino]-N,N,3-trimethyl-6-(2-methylpropyl)-2,5,8,20-tetraoxo-11,16-dioxa-1,4,7,19-tetrazabicyclo[19.3.0]tetracosane-18-carboxamide	1675870: Binding affinity to biotinylated TRF2 (unknown origin) by biolayer interferometry assay	kd	2.5000	uM
(2S)-1-[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-acetamido-4-methylpentanoyl]amino]propanoyl]amino]-4-methylpentanoyl]amino]propanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-methylpentanoyl]amino]-4-methylpentanoyl]amino]-3-hydroxybutanoyl]-N-[(2S)-1-amino-3-methyl-1-oxobutan-2-yl]pyrrolidine-2-carboxamide	1355116: Displacement of 5-((2R,6S,9S,12S,15S,18S,21S,24S)-3-((S)-2-((S)-1-amino-3-methyl-1-oxobutan-2-ylcarbamoyl)pyrrolidine-1-carbonyl)-15-(4-aminobutyl)-2-hydroxy-12-(4-hydroxybenzyl)-6,9,18,24-tetraisobutyl-21-methyl-5,8,11,14,17,20,23,26,29-nonaoxo-4,7,10,13,16,19,22,25,28-nonaazatetratriacontan-34-ylcarbamoyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid from TRF2 TRFH domain (unknown origin) after 30 mins by fluorescence polarization assay	ki	3.2000	uM
(2S)-1-[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-acetamido-4-methylpentanoyl]amino]propanoyl]amino]-4-methylpentanoyl]amino]-6-aminohexanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]-4-methylpentanoyl]amino]-3-hydroxybutanoyl]-N-[(2S)-1-amino-3-methyl-1-oxobutan-2-yl]pyrrolidine-2-carboxamide	1355116: Displacement of 5-((2R,6S,9S,12S,15S,18S,21S,24S)-3-((S)-2-((S)-1-amino-3-methyl-1-oxobutan-2-ylcarbamoyl)pyrrolidine-1-carbonyl)-15-(4-aminobutyl)-2-hydroxy-12-(4-hydroxybenzyl)-6,9,18,24-tetraisobutyl-21-methyl-5,8,11,14,17,20,23,26,29-nonaoxo-4,7,10,13,16,19,22,25,28-nonaazatetratriacontan-34-ylcarbamoyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid from TRF2 TRFH domain (unknown origin) after 30 mins by fluorescence polarization assay	ki	3.4000	uM
(3S,6S,9S,18S,21S)-9-[[3-(cyclobutylmethoxy)-5-phenylmethoxybenzoyl]amino]-N,N,3-trimethyl-6-(2-methylpropyl)-2,5,8,20-tetraoxo-11,16-dioxa-1,4,7,19-tetrazabicyclo[19.3.0]tetracosane-18-carboxamide	1675871: Binding affinity to TRFH domain of TRF2 (residues 42 to 245) (unknown origin) by FP based assay	ki	4.3000	uM
(2S)-1-[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-acetamido-4-methylpentanoyl]amino]propanoyl]amino]-4-methylpentanoyl]amino]-6-aminohexanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-methylpentanoyl]amino]pentanoyl]amino]-3-hydroxybutanoyl]-N-[(2S)-1-amino-3-methyl-1-oxobutan-2-yl]pyrrolidine-2-carboxamide	1355116: Displacement of 5-((2R,6S,9S,12S,15S,18S,21S,24S)-3-((S)-2-((S)-1-amino-3-methyl-1-oxobutan-2-ylcarbamoyl)pyrrolidine-1-carbonyl)-15-(4-aminobutyl)-2-hydroxy-12-(4-hydroxybenzyl)-6,9,18,24-tetraisobutyl-21-methyl-5,8,11,14,17,20,23,26,29-nonaoxo-4,7,10,13,16,19,22,25,28-nonaazatetratriacontan-34-ylcarbamoyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid from TRF2 TRFH domain (unknown origin) after 30 mins by fluorescence polarization assay	ki	4.7000	uM
(3S,6S,9S,18S,21S)-9-[(3-cyclobutyloxy-5-phenylmethoxybenzoyl)amino]-N,N,3-trimethyl-6-(2-methylpropyl)-2,5,8,20-tetraoxo-11,16-dioxa-1,4,7,19-tetrazabicyclo[19.3.0]tetracosane-18-carboxamide	1675871: Binding affinity to TRFH domain of TRF2 (residues 42 to 245) (unknown origin) by FP based assay	ki	4.9000	uM
(3S,6S,9S,18S,21S)-9-[(3-cyclopentyloxy-5-phenylmethoxybenzoyl)amino]-N,N,3-trimethyl-6-(2-methylpropyl)-2,5,8,20-tetraoxo-11,16-dioxa-1,4,7,19-tetrazabicyclo[19.3.0]tetracosane-18-carboxamide	1675871: Binding affinity to TRFH domain of TRF2 (residues 42 to 245) (unknown origin) by FP based assay	ki	5.1000	uM
(3S,6S,9S,18S,21S)-N,N,3-trimethyl-9-[[3-(2-methylpropoxy)-5-phenylmethoxybenzoyl]amino]-6-(2-methylpropyl)-2,5,8,20-tetraoxo-11,16-dioxa-1,4,7,19-tetrazabicyclo[19.3.0]tetracosane-18-carboxamide	1675871: Binding affinity to TRFH domain of TRF2 (residues 42 to 245) (unknown origin) by FP based assay	ki	5.2000	uM
(2S)-1-[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-acetamido-4-methylpentanoyl]amino]propanoyl]amino]-4-methylpentanoyl]amino]-6-aminohexanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-methylpentanoyl]amino]-4,4-dimethylpentanoyl]amino]-3-hydroxybutanoyl]-N-[(2S)-1-amino-3-methyl-1-oxobutan-2-yl]pyrrolidine-2-carboxamide	1355116: Displacement of 5-((2R,6S,9S,12S,15S,18S,21S,24S)-3-((S)-2-((S)-1-amino-3-methyl-1-oxobutan-2-ylcarbamoyl)pyrrolidine-1-carbonyl)-15-(4-aminobutyl)-2-hydroxy-12-(4-hydroxybenzyl)-6,9,18,24-tetraisobutyl-21-methyl-5,8,11,14,17,20,23,26,29-nonaoxo-4,7,10,13,16,19,22,25,28-nonaazatetratriacontan-34-ylcarbamoyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid from TRF2 TRFH domain (unknown origin) after 30 mins by fluorescence polarization assay	ki	6.1000	uM
(3S,6S,9S,18S,21S)-9-[[3-(cyclopentylmethoxy)-5-phenylmethoxybenzoyl]amino]-N,N,3-trimethyl-6-(2-methylpropyl)-2,5,8,20-tetraoxo-11,16-dioxa-1,4,7,19-tetrazabicyclo[19.3.0]tetracosane-18-carboxamide	1675871: Binding affinity to TRFH domain of TRF2 (residues 42 to 245) (unknown origin) by FP based assay	ki	6.9000	uM
(2S)-1-[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-acetamido-4-methylpentanoyl]amino]propanoyl]amino]-4-methylpentanoyl]amino]-6-aminohexanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-methylpentanoyl]amino]-3-phenylpropanoyl]amino]-3-hydroxybutanoyl]-N-[(2S)-1-amino-3-methyl-1-oxobutan-2-yl]pyrrolidine-2-carboxamide	1355116: Displacement of 5-((2R,6S,9S,12S,15S,18S,21S,24S)-3-((S)-2-((S)-1-amino-3-methyl-1-oxobutan-2-ylcarbamoyl)pyrrolidine-1-carbonyl)-15-(4-aminobutyl)-2-hydroxy-12-(4-hydroxybenzyl)-6,9,18,24-tetraisobutyl-21-methyl-5,8,11,14,17,20,23,26,29-nonaoxo-4,7,10,13,16,19,22,25,28-nonaazatetratriacontan-34-ylcarbamoyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid from TRF2 TRFH domain (unknown origin) after 30 mins by fluorescence polarization assay	ki	8.5000	uM
2-[3-[[(3S,6S,9S,18S,21S)-18-(dimethylcarbamoyl)-3-methyl-6-(2-methylpropyl)-2,5,8,20-tetraoxo-11,16-dioxa-1,4,7,19-tetrazabicyclo[19.3.0]tetracosan-9-yl]carbamoyl]-5-phenylmethoxyphenoxy]acetic acid	1675871: Binding affinity to TRFH domain of TRF2 (residues 42 to 245) (unknown origin) by FP based assay	ki	8.8000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, increases expression	3
Fluorouracil	increases expression	2
aristolochic acid I	increases expression	1
FR900359	decreases phosphorylation	1
TAK-243	increases sumoylation	1
triphenyl phosphate	affects expression	1
pirinixic acid	affects binding, increases activity, increases expression	1
2,4,5,2’,4’,5’-hexachlorobiphenyl	affects reaction, increases expression, affects cotreatment, decreases expression	1
3,4,5,3’,4’-pentachlorobiphenyl	decreases expression	1
vanadyl sulfate	decreases expression	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
Grape Seed Proanthocyanidins	affects cotreatment, increases expression	1
pazopanib	increases expression	1
Arsenic Trioxide	increases expression	1
Arsenic	decreases expression	1
Cadmium	increases abundance, increases expression	1
Catechin	affects cotreatment, increases expression	1
Cisplatin	decreases expression, increases reaction	1
Dimethyl Sulfoxide	affects cotreatment, decreases expression, increases expression	1
Doxorubicin	decreases expression	1
Formaldehyde	decreases expression	1
Ivermectin	decreases expression	1
Lead	decreases expression	1
Piroxicam	decreases expression, increases reaction	1
Tetradecanoylphorbol Acetate	affects reaction, increases expression	1
Tobacco Smoke Pollution	increases expression	1
Tretinoin	affects cotreatment, decreases expression, increases expression	1
Antirheumatic Agents	decreases expression	1
Cadmium Chloride	increases abundance, increases expression	1

ChEMBL screening assays

4 unique, capped per target: 4 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4150013	Binding	Displacement of 5-((2R,6S,9S,12S,15S,18S,21S,24S)-3-((S)-2-((S)-1-amino-3-methyl-1-oxobutan-2-ylcarbamoyl)pyrrolidine-1-carbonyl)-15-(4-aminobutyl)-2-hydroxy-12-(4-hydroxybenzyl)-6,9,18,24-tetraisobutyl-21-methyl-5,8,11,14,17,20,23,26,29-no	Cyclic Peptidic Mimetics of Apollo Peptides Targeting Telomeric Repeat Binding Factor 2 (TRF2) and Apollo Interaction. — *ACS Med Chem Lett*

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_WM80	HTC75 T19	Cancer cell line	Male
CVCL_WM81	HTC75 T4	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 TERF2 across ~30M SureChEMBL compounds — explore on Sugi Predict.