TERF1

Summary

TERF1 (telomeric repeat binding factor 1, HGNC:11728) is a protein-coding gene on chromosome 8q21.11, encoding Telomeric repeat-binding factor 1 (P54274). Binds the telomeric double-stranded 5’-TTAGGG-3’ repeat and negatively regulates telomere length. It is a selective cancer dependency (DepMap: 22.1% of cell lines).

This gene encodes a telomere specific protein which is a component of the telomere nucleoprotein complex. This protein is present at telomeres throughout the cell cycle and functions as an inhibitor of telomerase, acting in cis to limit the elongation of individual chromosome ends. The protein structure contains a C-terminal Myb motif, a dimerization domain near its N-terminus and an acidic N-terminus. Multiple transcripts of this gene are alternatively spliced products.

Source: NCBI Gene 7013 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 73 total
• Cancer dependency (DepMap): dependent in 22.1% of screened cell lines
• MANE Select transcript: NM_017489

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11728
Approved symbol	TERF1
Name	telomeric repeat binding factor 1
Location	8q21.11
Locus type	gene with protein product
Status	Approved
Aliases	PIN2, TRF1, TRF
Ensembl gene	ENSG00000147601
Ensembl biotype	protein_coding
OMIM	600951
Entrez	7013

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 14 protein_coding, 6 retained_intron, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000276602, ENST00000276603, ENST00000517390, ENST00000518695, ENST00000518874, ENST00000518961, ENST00000520783, ENST00000522018, ENST00000676483, ENST00000677031, ENST00000678358, ENST00000678518, ENST00000678860, ENST00000678912, ENST00000678997, ENST00000679115, ENST00000899325, ENST00000912757, ENST00000912758, ENST00000912759, ENST00000912760, ENST00000912761, ENST00000912762

RefSeq mRNA: 14 — MANE Select: NM_017489 NM_001410928, NM_001413364, NM_001413365, NM_001413366, NM_001413367, NM_001413368, NM_001413369, NM_001413370, NM_001413371, NM_001413372, NM_001413373, NM_001413374, NM_003218, NM_017489

CCDS: CCDS6210, CCDS6211, CCDS94314

Canonical transcript exons

ENST00000276603 — 10 exons

Exon	Start	End
ENSE00000980813	73013895	73013990
ENSE00000980815	73022216	73022302
ENSE00000980818	73030336	73030395
ENSE00001408652	73008864	73009205
ENSE00002096154	73045961	73048123
ENSE00002729434	73020684	73020805
ENSE00003466983	73024822	73024971
ENSE00003548417	73039116	73039219
ENSE00003592300	73026940	73027052
ENSE00003664180	73032042	73032133

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 95.37.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 37.8845 / max 955.6875, expressed in 1815 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
89370	29.1540	1812
89371	5.7373	556
89372	1.6616	486
89369	1.3316	478

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	95.37	gold quality
sural nerve	UBERON:0015488	91.97	gold quality
dorsal root ganglion	UBERON:0000044	91.78	gold quality
cauda epididymis	UBERON:0004360	91.70	gold quality
substantia nigra pars reticulata	UBERON:0001966	90.86	gold quality
germinal epithelium of ovary	UBERON:0001304	90.80	gold quality
seminal vesicle	UBERON:0000998	90.72	gold quality
ventricular zone	UBERON:0003053	90.59	gold quality
trigeminal ganglion	UBERON:0001675	90.55	gold quality
substantia nigra pars compacta	UBERON:0001965	90.46	gold quality
ganglionic eminence	UBERON:0004023	90.39	gold quality
tibial nerve	UBERON:0001323	90.26	gold quality
urethra	UBERON:0000057	90.13	gold quality
embryo	UBERON:0000922	89.99	gold quality
caput epididymis	UBERON:0004358	89.87	gold quality
superficial temporal artery	UBERON:0001614	89.81	gold quality
paraflocculus	UBERON:0005351	89.76	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	89.73	gold quality
lateral nuclear group of thalamus	UBERON:0002736	89.73	gold quality
lateral globus pallidus	UBERON:0002476	89.72	gold quality
synovial joint	UBERON:0002217	89.38	gold quality
entorhinal cortex	UBERON:0002728	89.32	gold quality
cranial nerve II	UBERON:0000941	89.27	gold quality
renal glomerulus	UBERON:0000074	89.23	gold quality
pigmented layer of retina	UBERON:0001782	89.23	gold quality
mucosa of stomach	UBERON:0001199	89.06	gold quality
penis	UBERON:0000989	88.90	gold quality
ovary	UBERON:0000992	88.74	gold quality
blood vessel layer	UBERON:0004797	88.74	gold quality
pylorus	UBERON:0001166	88.71	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-MTAB-10018	yes	1166.89
E-MTAB-9388	yes	314.72
E-MTAB-8060	yes	243.87
E-ANND-3	yes	6.70
E-MTAB-6819	no	934.91
E-MTAB-7008	no	663.17

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ATM, CEBPB, NFKB, NR3C1, POU5F1, STAT3, TBPL1

miRNA regulators (miRDB)

88 targeting TERF1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-8067	99.86	69.59	2260
HSA-MIR-383-3P	99.85	65.84	1359
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-4760-5P	99.80	69.88	1619

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 22.1% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• Pin2/TRF1 (TERF1) can specifically induce entry into mitosis and apoptosis, likely via a mechanism related to activation of caspase-3. (PMID:11313893)
• inhibition of Pin2/TRF1 in A-T cells is able to bypass the requirement for ATM in specifically restoring telomere shortening, the G(2)/M checkpoint defect, and radiosensitivity (PMID:11744712)
• Isoform PIN2 interacts with the human SALL1 gene product. (PMID:11751684)
• tumour growth does not seem to depend on cell proliferation but on TRF1 immunoexpression (PMID:11813863)
• The telomeric poly(ADP-ribose) polymerase, tankyrase 1, contains multiple binding sites for telomeric repeat binding factor 1 (TRF1) and a novel acceptor, 182-kDa tankyrase-binding protein (TAB182). (PMID:11854288)
• 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)
• Gastric carcinomas with high TRF1 expression may require a large quantity of hRap1/ (PMID:12007281)
• Identification of a tankyrase-binding motif in this protein (PMID:12080061)
• Down-regulation of TRF1, TRF2 and TIN2 genes is important to maintain telomeric DNA for gastric cancers. (PMID:12530079)
• the interaction between the TRF1 complex and POT1 affects the loading of POT1 on the single-stranded telomeric DNA, thus transmitting information about telomere length to the telomere terminus, where telomerase is regulated (PMID:12768206)
• the level of telomeric repeat binding factor 1 expression may be helpful prognostically for patients with adrenal cortical cancers (PMID:12915656)
• Results provide evidence that specific ankyrin repeat cluster-TRF1 interactions play roles in the essential catalytic function of tankyrase 1. (PMID:14966275)
• hRap1 negatively regulates telomere length in vivo and the linker region of hRap1 may modulate the recruitment of negative regulators of telomere length (PMID:15100233)
• Partial knockdown of TIN2 by small hairpin RNA in a telomerase-positive cell line resulted in telomere elongation, which is typical of reduced TRF1 function. (PMID:15133513)
• TIN2 binds TRF1 and TRF2 simultaneously and stabilizes the TRF2 complex on telomeres (PMID:15316005)
• Results report the detection of new alternative transcripts of the TRF1/Pin2 gene in peripheral blood lymphocytes resulting from a 76 nucleotide insertion. (PMID:15389875)
• 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)
• Loss of TRF1 expression capability, as a result of down-regulation of TRF1 expression in malignant gliomas cells, may play a role in the malignant progression of astroglial brain tumors. (PMID:15792519)
• Fbx4 is a central regulator of Pin2/TRF1 protein abundance and alterations in the stability of Pin2/TRF1 can have a dramatic impact on telomere length (PMID:16275645)
• CONCLUSION: hTRF1 mutation is probably not one of the main factors for telomerase activation in malignant hematopoietic disease. (PMID:16358369)
• TRF1 protein levels are related to the activity of telomerase and may have a role in human acute leukemia (PMID:16421973)
• TRF1 is able to specifically recognize telomeric binding sites located within nucleosomes, forming a ternary complex. (PMID:16756990)
• An increase in TIN2 expression in adult T-cell leukemia which may be a markerse for disease progression. (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)
• significantly lower expression of TRF1 was associated with non-small cell lung cancer (PMID:17020976)
• tankyrase1 is a poly(ADP-ribose) polymerase with roles in telomere length control by the TRF1 component of the shelterin complex (PMID:17561506)
• 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)
• TRF1 association with telomeres induced by ATM inhibition is abrogated in cells lacking MRE11 or NBS1, suggesting that MRN and ATM function in the same pathway controlling TRF1 binding to telomeres (PMID:17694070)
• These results suggest that c-Myc may be involved in the regulation of telomere length through its direct binding with TRF1/PIN2. (PMID:17765874)
• TRF1 and TRF2 bind to the dsDNA of telomeres, whereas POT1 binds to the ssDNA portion (PMID:18178559)
• 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)
• even without TRF1 PARsylation, this mutant tankyrase 1 seemed to loosen the closed structure of the telomeric heterochromatin (PMID:18221737)
• CK2-mediated phosphorylation of TRF1 plays an important role in modulating telomere length homeostasis by determining the levels of TRF1 at telomeres (PMID:18347021)
• down-regulation of telomeric repeat binding factor 1 expression appeared in lung cancer tissue. (PMID:18397896)
• Plk1 interacts with and phosphorylates TRF1 and Plk1-mediated phosphorylation is involved in both TRF1 overexpression-induced apoptosis and its telomeric DNA binding ability (PMID:18625707)
• RLIM represents a new pathway for telomere maintenance by modulating the level of TRF1 at telomeres. (PMID:19164295)
• Results show that hPinX1 regulates the nucleolar accumulation and telomeric association of TRF1. (PMID:19265708)
• Gene deletion experiments showed that efficient duplication of telomeres requires the shelterin component TRF1. (PMID:19596237)
• nuclear localization signal and nuclear export signal sequences in NSCLCs patients did not have mutations. (PMID:19746267)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	terf1	ENSDARG00000058710
mus_musculus	Terf1	ENSMUSG00000025925
rattus_norvegicus	Terf1	ENSRNOG00000007291

Paralogs (1): TERF2 (ENSG00000132604)

Protein

Protein identifiers

Telomeric repeat-binding factor 1 — P54274 (reviewed: P54274)

Alternative names: NIMA-interacting protein 2, TTAGGG repeat-binding factor 1, Telomeric protein Pin2/TRF1

All UniProt accessions (8): P54274, A0A7I2V3N9, A0A7I2V5E0, A0A7I2V5I6, A0A7I2V5T5, A0A7I2YQE7, E5RFJ5, E7EWM7

UniProt curated annotations — full annotation on UniProt →

Function. Binds the telomeric double-stranded 5’-TTAGGG-3’ repeat and negatively regulates telomere length. Involved in the regulation of the mitotic spindle. 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.

Subunit / interactions. Homodimer; can contain both isoforms. Found in a complex with POT1; TINF2 and TNKS1. Interacts with ATM, TINF2, TNKS1, TNKS2, PINX1, NEK2 and MAPRE1. Component of the shelterin complex (telosome) composed of TERF1, TERF2, TINF2, TERF2IP ACD and POT1. Interacts with RLIM (via N-terminus). Interacts with FBXO4. Interaction with TINF2 protects against interaction with FBXO4 and subsequent polyubiquitination and proteasomal degradation. Interacts with GNL3L; this interaction promotes homodimerization. Interacts with TIN2. Interacts with RTEL1. Interactions with GNL3L and TIN2 are mutually exclusive. Interacts with CCDC79/TERB1. Interacts with TRIOBP isoform 1; mediates TERF1 localization to the centrosome.

Subcellular location. Nucleus. Cytoplasm. Cytoskeleton. Spindle. Chromosome. Telomere.

Tissue specificity. Highly expressed and ubiquitous. Isoform Pin2 predominates.

Post-translational modifications. Phosphorylated preferentially on Ser-219 in an ATM-dependent manner in response to ionizing DNA damage. ADP-ribosylation by TNKS1 or TNKS2 diminishes its ability to bind to telomeric DNA. Ubiquitinated by RLIM/RNF12, leading to its degradation by the proteasome. Ubiquitinated by a SCF (SKP1-CUL1-F-box protein) ubiquitin-protein ligase complex, leading to its degradation by the proteasome.

Domain organisation. The acidic N-terminal domain binds to the ankyrin repeats of TNKS1 and TNKS2. The C-terminal domain binds microtubules. The TRFH dimerization region mediates the interaction with TINF2. The HTH domain is an independent structural unit and mediates binding to telomeric DNA.

Induction. Expression is tightly regulated during the cell cycle; levels are low in G1 and S phase and increase during G2 phase and mitosis.

Isoforms (2)

UniProt ID	Names	Canonical?
P54274-1	1, TRF1	yes
P54274-2	2, Pin2

RefSeq proteins (14): NP_001397857, NP_001400293, NP_001400294, NP_001400295, NP_001400296, NP_001400297, NP_001400298, NP_001400299, NP_001400300, NP_001400301, NP_001400302, NP_001400303, NP_003209, NP_059523* (*=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
IPR036507	Telomere_rpt-bd_fac_dimer_sf	Homologous_superfamily
IPR052450	TRBD-Containing_Protein	Family

Pfam: PF00249, PF08558

UniProt features (50 total): helix 13, mutagenesis site 9, strand 6, region of interest 5, modified residue 3, cross-link 3, compositionally biased region 2, sequence conflict 2, initiator methionine 1, chain 1, splice variant 1, domain 1, DNA-binding region 1, turn 1, short sequence motif 1

Structure

Experimental structures (PDB)

58 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
9HCZ	X-RAY DIFFRACTION	1.55
9HCX	X-RAY DIFFRACTION	1.69
9HCP	X-RAY DIFFRACTION	1.7
9HCT	X-RAY DIFFRACTION	1.7
9HD1	X-RAY DIFFRACTION	1.73
9HCL	X-RAY DIFFRACTION	1.87
9HD9	X-RAY DIFFRACTION	1.87
9HF9	X-RAY DIFFRACTION	1.9
9HCN	X-RAY DIFFRACTION	1.93
9HCY	X-RAY DIFFRACTION	1.93
9HD0	X-RAY DIFFRACTION	1.93
9HCR	X-RAY DIFFRACTION	1.93
9HCQ	X-RAY DIFFRACTION	1.96
1W0T	X-RAY DIFFRACTION	2
3BQO	X-RAY DIFFRACTION	2
9HFG	X-RAY DIFFRACTION	2.02
9HFE	X-RAY DIFFRACTION	2.04
9HFA	X-RAY DIFFRACTION	2.05
9HFF	X-RAY DIFFRACTION	2.06
9HCU	X-RAY DIFFRACTION	2.07
9HD2	X-RAY DIFFRACTION	2.07
9HCV	X-RAY DIFFRACTION	2.08
9HCW	X-RAY DIFFRACTION	2.08
5WIR	X-RAY DIFFRACTION	2.1
5XUP	X-RAY DIFFRACTION	2.1
9HDA	X-RAY DIFFRACTION	2.1
9HFH	X-RAY DIFFRACTION	2.12
9HFD	X-RAY DIFFRACTION	2.15
9HLT	X-RAY DIFFRACTION	2.16
9HF4	X-RAY DIFFRACTION	2.17

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P54274-F1	71.60	0.48

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 (6): 2, 11, 219, 213, 325, 366

Mutagenesis-validated functional residues (9):

Position	Phenotype
74	abolishes dimerization and telomere binding; when associated with p-75.
75	abolishes dimerization and telomere binding; when associated with d-74.
77	abolishes telomere binding.
81	abolishes telomere binding.
90	diminishes telomere binding.
115	loss of interaction with fbxo4.
120	loss of interaction with fbxo4.
219	loss of phosphorylation; induction of mitotic entry and apoptosis and increased radiation hypersensitivity of ataxia-tel
219	fails to induce apoptosis and decreases radiation hypersensitivity of ataxia-telangiectasia cells (phospho-mimicking mut

Function

Pathways and Gene Ontology

Reactome pathways

28 pathways

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

MSigDB gene sets: 258 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_DN, GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_DN, GOBP_MEIOTIC_CHROMOSOME_SEGREGATION, GOBP_RNA_TEMPLATED_DNA_BIOSYNTHETIC_PROCESS, GOBP_CHROMOSOME_ORGANIZATION, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, BIOCARTA_TEL_PATHWAY, GOBP_NEGATIVE_REGULATION_OF_TELOMERE_MAINTENANCE_VIA_TELOMERASE, PID_TELOMERASE_PATHWAY, CCAWYNNGAAR_UNKNOWN, DACOSTA_UV_RESPONSE_VIA_ERCC3_XPCS_DN, GOBP_TELOMERE_CAPPING, REACTOME_MEIOTIC_SYNAPSIS, GOBP_CELL_CYCLE_DNA_REPLICATION, GOBP_CHROMOSOME_LOCALIZATION

GO Biological Process (18): telomere maintenance (GO:0000723), telomere maintenance via telomerase (GO:0007004), negative regulation of DNA replication (GO:0008156), response to xenobiotic stimulus (GO:0009410), telomere capping (GO:0016233), positive regulation of telomere maintenance (GO:0032206), negative regulation of telomere maintenance via telomerase (GO:0032211), negative regulation of telomere maintenance via semi-conservative replication (GO:0032214), meiotic telomere clustering (GO:0045141), cell division (GO:0051301), telomeric D-loop disassembly (GO:0061820), t-circle formation (GO:0090656), negative regulation of telomere maintenance via telomere lengthening (GO:1904357), positive regulation of shelterin complex assembly (GO:1904792), negative regulation of establishment of protein localization to telomere (GO:1904850), negative regulation of establishment of RNA localization to telomere (GO:1904911), negative regulation of establishment of protein-containing complex localization to telomere (GO:1904914), negative regulation of telomeric D-loop disassembly (GO:1905839)

GO Molecular Function (11): DNA binding (GO:0003677), double-stranded telomeric DNA binding (GO:0003691), microtubule binding (GO:0008017), DNA binding, bending (GO:0008301), telomeric repeat DNA binding (GO:0042162), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), ankyrin repeat binding (GO:0071532), G-rich strand telomeric DNA binding (GO:0098505), telomerase activity (GO:0003720), protein binding (GO:0005515)

GO Cellular Component (12): chromosome, telomeric region (GO:0000781), nuclear telomere cap complex (GO:0000783), fibrillar center (GO:0001650), nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), spindle (GO:0005819), nuclear body (GO:0016604), shelterin complex (GO:0070187), chromosome (GO:0005694), cytoplasm (GO:0005737), cytoskeleton (GO:0005856)

Reactome top-level categories

Rollup of top-12 pathways:

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

Rollup of top GO terms by namespace:

Category	Terms
intracellular membraneless organelle	5
cellular anatomical structure	3
telomere maintenance via telomere lengthening	2
telomere maintenance	2
negative regulation of telomere maintenance	2
negative regulation of biological process	2
nuclear lumen	2
DNA metabolic process	1
telomere organization	1
telomerase activity	1
RNA-templated DNA biosynthetic process	1
telomere-telomerase complex assembly	1
DNA replication	1
regulation of DNA replication	1
negative regulation of DNA metabolic process	1
response to chemical	1
regulation of telomere maintenance	1
positive regulation of DNA metabolic process	1
positive regulation of chromosome organization	1
telomere maintenance via telomerase	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
telomere localization	1
chromosome organization involved in meiotic cell cycle	1
chromosome localization to nuclear envelope involved in homologous chromosome segregation	1
cellular process	1
telomeric loop disassembly	1
formation of extrachromosomal circular DNA	1
telomere maintenance via telomere trimming	1
regulation of telomere maintenance via telomere lengthening	1
positive regulation of protein-containing complex assembly	1
shelterin complex assembly	1
regulation of shelterin complex assembly	1
establishment of protein localization to telomere	1
regulation of establishment of protein localization to telomere	1
negative regulation of establishment of protein localization	1

Protein interactions and networks

STRING

2146 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TERF1	TINF2	Q9BSI4	999
TERF1	TNKS	O95271	999
TERF1	POT1	Q9NUX5	999
TERF1	ACD	Q96AP0	998
TERF1	TERF2IP	Q9NYB0	997
TERF1	TPP1	O14773	993
TERF1	TNKS2	Q9H2K2	992
TERF1	NUPR2	A6NF83	991
TERF1	TERF2	Q15554	988
TERF1	WRN	Q14191	944
TERF1	TERT	O14746	926
TERF1	RTEL1	Q9NZ71	911
TERF1	DKC1	O60832	885
TERF1	ATM	Q13315	884
TERF1	DCLRE1B	Q9H816	882

IntAct

341 interactions, top by confidence:

A	B	Type	Score
TINF2	TERF1	psi-mi:“MI:0915”(physical association)	0.940
TERF1	TINF2	psi-mi:“MI:0915”(physical association)	0.940
TERF1	PINX1	psi-mi:“MI:0915”(physical association)	0.880
MAPRE1	TERF1	psi-mi:“MI:0915”(physical association)	0.650
TERF1	MAPRE1	psi-mi:“MI:0915”(physical association)	0.650
ATM	TERF1	psi-mi:“MI:0915”(physical association)	0.610
TERF1	TERF1	psi-mi:“MI:0915”(physical association)	0.550
TERF1	YWHAG	psi-mi:“MI:0915”(physical association)	0.550
SHFL	TERF1	psi-mi:“MI:0915”(physical association)	0.510
TERF1	SUPT5H	psi-mi:“MI:0915”(physical association)	0.510
RBMY1A1	TERF1	psi-mi:“MI:0915”(physical association)	0.510
TERF1	RNF10	psi-mi:“MI:0915”(physical association)	0.510
TERF1	LRSAM1	psi-mi:“MI:0915”(physical association)	0.510
TERF1	TRMT1	psi-mi:“MI:0915”(physical association)	0.510
TERF1	SOAT1	psi-mi:“MI:0915”(physical association)	0.510
TERF1	MDH1	psi-mi:“MI:0915”(physical association)	0.510
LDHB	TERF1	psi-mi:“MI:0915”(physical association)	0.510
TERF1	PRDX6	psi-mi:“MI:0915”(physical association)	0.510
TERF1	AMPD2	psi-mi:“MI:0915”(physical association)	0.510
TERF1	CUSTOS	psi-mi:“MI:0915”(physical association)	0.510
TERF1	PAK4	psi-mi:“MI:0915”(physical association)	0.510
TERF1	CRYBB1	psi-mi:“MI:0915”(physical association)	0.510
SH3BP1	TERF1	psi-mi:“MI:0915”(physical association)	0.510
TPI1	TERF1	psi-mi:“MI:0915”(physical association)	0.510
DDX23	TERF1	psi-mi:“MI:0915”(physical association)	0.510
EPB41L1	TERF1	psi-mi:“MI:0915”(physical association)	0.510
TERF1	NAP1L1	psi-mi:“MI:0915”(physical association)	0.510

BioGRID (485): EP300 (Affinity Capture-Western), TERF1 (Affinity Capture-MS), POT1 (Affinity Capture-MS), TINF2 (Affinity Capture-MS), TNKS2 (Affinity Capture-MS), TNKS (Affinity Capture-MS), TERF2IP (Affinity Capture-MS), ACD (Affinity Capture-MS), FOXM1 (Affinity Capture-MS), TERF1 (Affinity Capture-MS), TERF1 (Affinity Capture-MS), TERF1 (Affinity Capture-MS), TERF1 (Affinity Capture-MS), TERF1 (Affinity Capture-MS), XPO1 (Affinity Capture-MS)

ESM2 similar proteins: A0A1B0GUJ8, A1A5R7, A2CJ06, A7E3N2, B1H224, B8QB46, D3Z8Y2, D3ZSP7, O55036, P0CG32, P54274, P70371, Q14BQ3, Q29RJ0, Q2HJ46, Q2T9U5, Q3TTP0, Q4R8X0, Q4R9F7, Q4VA55, Q5DTT8, Q5RBH9, Q5TKR9, Q5U310, Q5ZIX8, Q6DJS0, Q6ZQF7, Q71M44, Q7Z2W4, Q7Z7J5, Q80VH0, Q80VM8, Q8BMD7, Q8BZ21, Q8CCG4, Q8CDN1, Q8JZW8, Q8ND61, Q8TE76, Q8VD24

Diamond homologs: B4FT40, C0HIA3, F4I7L1, F4IEY4, O55036, P08283, P27806, P37218, P40267, P54274, P70371, Q15554, Q6WLH3, Q6WLH4, Q6WS85, Q8VWK4, Q8W119, Q9FJW5, Q9M2X3, Q9M5W4, Q9PU53, Q43386, Q6C9I6, O35144, Q10274, P23444, P26568, P26569, Q00423, Q08865

SIGNOR signaling

12 interactions.

A	Effect	B	Mechanism
ATM	“up-regulates activity”	TERF1	phosphorylation
CSNK2A1	up-regulates	TERF1	phosphorylation
PLK1	up-regulates	TERF1	phosphorylation
TERB1	“up-regulates activity”	TERF1	relocalization
TERF1	“form complex”	“Shelterin complex”	binding
NCAPH2	“up-regulates activity”	TERF1	binding
NEK7	“up-regulates quantity by stabilization”	TERF1	phosphorylation
NEK7	“up-regulates activity”	TERF1	phosphorylation
NEK7	“up-regulates quantity”	TERF1	phosphorylation
TNKS2	“down-regulates activity”	TERF1	ADP-ribosylation
TNKS	“down-regulates activity”	TERF1	ADP-ribosylation
AURKB	“up-regulates activity”	TERF1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 173 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
Gluconeogenesis	5	17.7×	2e-03
Glycolysis	6	13.8×	1e-03
HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand	6	9.4×	5e-03
Recycling pathway of L1	5	9.0×	9e-03
The role of GTSE1 in G2/M progression after G2 checkpoint	6	7.8×	6e-03
Recruitment of NuMA to mitotic centrosomes	7	6.6×	6e-03

GO biological processes:

GO term	Partners	Fold	FDR
canonical glycolysis	6	25.7×	1e-04
glycolytic process	7	16.4×	1e-04
cellular response to heat	7	14.7×	2e-04
microtubule cytoskeleton organization	9	6.7×	3e-03
protein stabilization	11	4.5×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	36
Likely benign	5
Benign	20

Top pathogenic / likely-pathogenic (0)

SpliceAI

1601 predictions. Top by Δscore:

Variant	Effect	Δscore
8:73009202:GAGG:G	donor_gain	1.0000
8:73009203:AGGGT:A	donor_loss	1.0000
8:73009204:GG:G	donor_gain	1.0000
8:73009204:GGGT:G	donor_loss	1.0000
8:73009205:GG:G	donor_gain	1.0000
8:73009206:G:GG	donor_gain	1.0000
8:73009206:GTGA:G	donor_loss	1.0000
8:73012932:G:GG	donor_gain	1.0000
8:73013891:TTA:T	acceptor_loss	1.0000
8:73013892:TA:T	acceptor_loss	1.0000
8:73013893:A:AG	acceptor_gain	1.0000
8:73013893:AGCTA:A	acceptor_loss	1.0000
8:73013894:G:GA	acceptor_gain	1.0000
8:73013894:GC:G	acceptor_gain	1.0000
8:73013894:GCT:G	acceptor_gain	1.0000
8:73013894:GCTA:G	acceptor_gain	1.0000
8:73013894:GCTAT:G	acceptor_gain	1.0000
8:73013991:GT:G	donor_loss	1.0000
8:73013992:T:A	donor_loss	1.0000
8:73020672:T:A	acceptor_gain	1.0000
8:73020679:A:AG	acceptor_gain	1.0000
8:73020680:A:AG	acceptor_gain	1.0000
8:73020681:A:G	acceptor_gain	1.0000
8:73020681:AAGAT:A	acceptor_gain	1.0000
8:73020682:A:AG	acceptor_gain	1.0000
8:73020682:AGAT:A	acceptor_gain	1.0000
8:73020683:G:GA	acceptor_gain	1.0000
8:73020683:GA:G	acceptor_gain	1.0000
8:73020683:GAT:G	acceptor_gain	1.0000
8:73020683:GATG:G	acceptor_gain	1.0000

AlphaMissense

2937 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:73046024:T:A	W403R	0.997
8:73046024:T:C	W403R	0.997
8:73046076:T:C	L420S	0.996
8:73046086:A:C	R423S	0.996
8:73046086:A:T	R423S	0.996
8:73046092:G:C	R425S	0.996
8:73046092:G:T	R425S	0.996
8:73045964:T:A	W383R	0.995
8:73045964:T:C	W383R	0.995
8:73045989:T:C	L391S	0.995
8:73046026:G:C	W403C	0.995
8:73046026:G:T	W403C	0.995
8:73046085:G:C	R423T	0.995
8:73046087:T:A	W424R	0.995
8:73046087:T:C	W424R	0.995
8:73046080:A:C	K421N	0.994
8:73046080:A:T	K421N	0.994
8:73046091:G:C	R425T	0.993
8:73009115:T:A	W77R	0.992
8:73009115:T:C	W77R	0.992
8:73046079:A:T	K421I	0.992
8:73045966:G:C	W383C	0.990
8:73045966:G:T	W383C	0.990
8:73046061:G:C	R415P	0.990
8:73046085:G:T	R423I	0.990
8:73022216:G:C	A180P	0.989
8:73046082:A:C	D422A	0.989
8:73009107:C:A	A74D	0.988
8:73046051:T:C	F412L	0.988
8:73046053:C:A	F412L	0.988

dbSNP variants (sampled 300 via entrez): RS1000051933 (8:73041743 A>C), RS1000106245 (8:73048622 C>A), RS1000116440 (8:73026335 A>G), RS1000277204 (8:73026070 C>T), RS1000311354 (8:73010657 G>A), RS1000480469 (8:73019577 G>A,C), RS1000519872 (8:73030040 C>T), RS1000599416 (8:73025324 G>A), RS1000611309 (8:73024617 T>C), RS1000768001 (8:73019735 C>A), RS1000855868 (8:73016914 A>C), RS1000866228 (8:73012515 C>A,G), RS1000893655 (8:73037465 A>G), RS1001059750 (8:73042702 A>G), RS1001113826 (8:73038057 T>C)

Disease associations

OMIM: gene MIM:600951 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST001438_7	Crohn’s disease	2.000000e-08
GCST008366_6	Leukocyte telomere length	7.000000e-15
GCST011828_2	Telomere length	9.000000e-13
GCST90000047_158	Age at first sexual intercourse	7.000000e-10

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009749	age at first sexual intercourse measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Ethanol	increases expression, affects reaction, decreases reaction	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
aristolochic acid I	decreases expression	1
FR900359	decreases phosphorylation	1
bisphenol F	affects cotreatment, increases expression	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	increases expression, affects cotreatment	1
geraniol	decreases expression	1
IMOL S-140	increases expression	1
2,4,5,2’,4’,5’-hexachlorobiphenyl	decreases expression, affects cotreatment, affects reaction, increases expression	1
beta-lapachone	decreases expression	1
sodium arsenite	affects expression	1
3,4,5,3’,4’-pentachlorobiphenyl	affects cotreatment, affects reaction, increases expression, decreases expression	1
4-hydroxy-2-nonenal	decreases expression	1
beta-methylcholine	affects expression	1
tebuconazole	decreases expression	1
pterostilbene	decreases reaction, increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment	1
dorsomorphin	affects cotreatment, decreases expression	1
NSC668394	increases expression	1
Resveratrol	affects localization	1
Sunitinib	increases expression	1
Arsenic Trioxide	increases expression	1
Vorinostat	decreases expression	1
Amiodarone	increases expression	1
Atrazine	decreases expression	1
Benzo(a)pyrene	affects methylation	1
Dexamethasone	affects cotreatment, increases expression	1
Dimethyl Sulfoxide	affects cotreatment, affects reaction, increases expression	1

Cellosaurus cell lines

4 cell lines: 3 embryonic stem cell, 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_C3LH	WAe009-A-95	Embryonic stem cell	Female
CVCL_C3LI	WAe009-A-96	Embryonic stem cell	Female
CVCL_C3LJ	WAe009-A-97	Embryonic stem cell	Female
CVCL_F0KK	U-2 OS H2B-GFP+mCherry-TRF1	Cancer cell line	Female

Clinical trials (associated diseases)

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