TERF2 (telomeric repeat binding factor 2)

2013-02-01 Molly L Bristol , Claire P Bailey , Lynne W Elmore Affiliation

Department of Pathology, Virginia Commonwealth University, Richmond, Virginia, USA

Identity

HGNC

TERF2

LOCATION

16q22.1

LOCUSID

7014

ALIAS

TRBF2,TRF2

FUSION GENES

Show Gene Fusions

DNA/RNA

Human TERF2 is alternatively spliced, resulting in 8 protein encoding transcripts. Figure adapted from Flicek et al. 2012.

Description

The human TERF2 gene spans a length of 53011 bp. The TERF2 structural gene is composed of 10 exons.

Transcription

Human TERF2 is alternatively spliced, resulting in 12 transcripts, 8 of which are protein encoding.
TERF2-001: 2951 bp in length, with a translational length of 500 residues.
TERF2-002: 1112 bp in length, with a translational length of 251 residues.
TERF2-003: 554 bp in length, with no protein product.
TERF2-004: 556 bp in length, with no protein product.
TERF2-005: 513 bp in length, with a translational length of 60 residues; transcript undergoes nonsense-mediated decay.
TERF2-006: 917 bp in length, with a translational length of 283 residues.
TERF2-008: 791 bp in length, with a translational length of 49 residues.
TERF2-009: 573 bp in length, with a translational length of 99 residues; transcript undergoes nonsense mediated decay.
TERF2-010: 316 bp in length, with no protein product.
TERF2-011: 1107 bp in length, with no protein product.
TERF2-012: 431 bp in length, with a translational length of 144 residues.
TERF2-013: 669 bp in length, with a translational length of 206 residues.
(Flicek et al., 2012).

Pseudogene

This gene has a pseudogene, TERF2IPP1, telomeric repeat binding factor 2 interacting protein pseudogene 1, located on chromosome 22q11.2 (Seal et al., 2011).

Proteins

Homodimer. Component of the shelterin complex (telosome) composed of TERF1, TERF2, TIN2, TPP1, RAP1 and POT1. Figure adapted from de Lange 2005, and Oeseburg et al. 2010.

Description

Of the 12 TERF2 transcripts, 8 encode for proteins, and 2 of these are subject to nonsense-mediated decay. Among splice variants: isoform 1 is 500 aa in length, mass 55.6 kDa; isoform 2 is 251 aa in length, mass 28.3 kDa; isoform 6 is 283 aa in length, mass 31.5 kDa; and isoform 13 is 206 aa in length, mass 22.9 kDa (Uhlen et al., 2010).

Expression

Ubiquitous. There are high levels of TERF2 expression in spleen, thymus, prostate, uterus, testes, brain, kidney, lung, liver, small intestine, colon, and peripheral blood leukocytes (Jung et al., 2004; Sugiura et al., 2003; UniProt, 2012).

Localisation

TERF2 colocalizes with telomeric DNA in the nucleus of cells at interphase, and is located at telomeres on chromosome ends during metaphase (Ye et al., 2010). TERF2 has also been found in peripheral nerve axons (Jung et al., 2004).

Function

TERF2 is a component of the telomere-specific protein complex called shelterin or telosome, which coats mammalian telomeric DNA (Kim et al., 2009). TERF2 is a homodimer, which binds to the double-stranded 5-TTAGGG-3 repeat in telomeres (van Steensel et al., 1998). Its primary role is the maintenance of telomere length, structure, and protection against end-to-end fusion of chromosomes. TERF2 induces the formation of telomere-loops (t-loops); without its protection, telomeres are no longer hidden from DNA repair pathways and these ends could be subject to non-homologous end joining (NHEJ) of chromosomes during metaphase (Wang et al., 2004). TERF2 causes the 3 single-stranded overhang to tuck under the double stranded TTAGGG repeat, thus shielding chromosomes from incorrect processing. TERF2 also works together with the exonuclease Apollo as a negative regulator of telomere length (Ye et al., 2010). TERF2 differs from TERF1 in that its N terminus is basic rather than acidic (provided by RefSeq, Jul 2008).

Homology

Significant TERF2 sequence homology is shared among human (H.sapiens), chimpanzee (P.troglodytes), Rhesus monkey (M.mulatta), dog (C.lupus), cow (B.taurus), mouse (M.musculus), and rat (R.norvegicus). Conserved domains in protein sequences include: the Telomeric Repeat binding Factor domain, the RAP1 binding motif of telomere repeat binding factor, and the SWI3, ADA2, N-CoR and TFIIIB DNA-binding domains, which consist of repeats containing the G/C rich motif (Geer et al., 2010).

Mutations

Note

According to the January 2013, NCBI dbSNP database, there are 488 known SNPs in the human TERF2 gene. SNPs associated with TERF2 affect telomere length and chromosomal stability by influencing gene expression or protein configuration at telomeres.

Implicated in

Entity name

Various pathological conditions

Note

The dysregulation of TERF2 has been implicated in the susceptibility of a number of human diseases and pathological disorders. Such implications include age- and cancer-related conditions.

Entity name

Adult T-cell leukemia

Note

TERF2 was found to be overexpressed in T-cell leukemia cell lines. TERF2 expression levels were found to be highest in primary leukemia cells from patients with M0 and M1 subtypes of acute myelogenous leukemia (AML) compared with normal controls and other subtypes of AML (Chen et al., 2008; Jiao et al., 2007).

Prognosis

Increased TERF2 expression levels were found in T-cell leukemia cell lines and AML patients with poor prognosis, suggesting that TRF2 expression might be related to the prognosis of leukemia (Chen et al., 2008; Jiao et al., 2007).

Entity name

Breast cancer

Note

In vitro models suggest that expression of TERF2 protein increases during mammary cancer progression. However, some data indicate that elevated expression of TERF2 is not a frequent occurrence during the transformation of breast cancer cells in vivo. Conversely, higher levels of TERF2 protein may protect advanced cancer cells with critically short telomeres, and shorter telomeres in breast cancer cells correlate with a higher TNM stage (Diehl et al., 2011).

Prognosis

Shorter telomeres correlate with advanced stages in breast cancer. Furthermore, elevated TERF2 levels are found in advanced breast cancer with short telomeres, suggesting TERF2 levels may correlate with breast cancer progression and prognosis (Diehl et al., 2011).

Entity name

Werner syndrome

Note

Telomere dysfunction has been proposed to contribute to the pathogenesis of Werner syndrome. The Werner syndrome protein (WRN) is a nuclear protein with helicase and exonuclease activities, whose loss-of-function mutations are associated with the premature aging and the cancer-prone disease, Werner syndrome. WRN functions at telomeres and interacts with TERF2. TERF2 has an N-terminal domain which plays a key role in the prevention of telomere shortening. Expression of TRF2(DeltaB), lacks this key domain, and leads to the formation of telomeric circles, telomere shortening, and cell senescence. The TRF2(DeltaB) pathway requires WRN helicase (Jog et al., 2011; Li et al., 2008).

Prognosis

Expression of TRF2(DeltaB) leads to excessive telomere shortening and cellular senescence, thus contributing to the pathogenesis of Werner syndrome (Jog et al., 2011; Li et al., 2008).

Entity name

Lung and bronchial cancer

Note

Telomere shortening is an early event in lung and bronchial carcinogenesis, leading to DNA damage responses (DDR). As telomere attrition occurs, genetic instability increases, thus facilitating malignant progression. When telomeres reach a critical length, expression of TERF2 increases progressively and correlates with progression from dysplasia to squamous invasive carcinoma and from atypical alveolar hyperplasia to invasive adenocarcinoma (Frias et al., 2008; Hosgood et al., 2009; Lantuejoul et al., 2010).

Prognosis

Telomere attrition occurs at an early stage of lung carcinogenesis as an initiating event and is preceded by TERF2 overexpression for telomere stabilization. Evidence suggests that telomere length and genetic variance of TERF2 and other telomere maintenance genes may be associated with an increased risk of developing lung cancer and a poorer prognosis (Frias et al., 2008; Hosgood et al., 2009; Lantuejoul et al., 2010).

Entity name

Colorectal cancer

Note

Overexpression of TERF2 protein has been observed in colorectal carcinoma tissue. Experimental data suggests that siRNA silencing of TERF2 expression significantly inhibited SW480 cell proliferation and colony formation; moreover, defective TERF2 induced apoptosis and increased chromosomal instability in SW480 cells (Dong et al., 2009).

Prognosis

TERF2 is overexpressed in colorectal carcinoma and siRNA TERF2 inhibition reduced tumorigenesis of colorectal cancer, suggesting a new target for the development of anti-cancer therapy for colorectal carcinoma (Dong et al., 2009).

Entity name

Age-dependent telomere shortening

Note

TERF2 alterations permit the progressive reduction in the length of telomeres at the termini of eukaryotic chromosomes, which occur as part of cellular aging.

Prognosis

Shortening of telomeres can initiate DNA damage response mechanisms, leading to cell cycle arrest, cell death, or cellular senescence whereby normal cells irreversibly lose their ability to divide (De Boeck et al., 2009; Mikhelson and Gamaley, 2012).

Entity name

Type 2 - Diabetes mellitus

Note

Leukocyte telomere length shortening has recently been associated with type 2 diabetes mellitus (T2D). tSNPs within TERF2 were associated with T2D risk (Zee et al., 2011).

Article Bibliography

Pubmed ID	Last Year	Title	Authors
18422278	2008	[Expression of telomere binding factor 2 (TRF2) on leukemia cell lines and primary leukemia cells].	Chen XH et al
19142887	2009	Telomere-associated proteins: cross-talk between telomere maintenance and telomere-lengthening mechanisms.	De Boeck G et al
20625812	2011	Elevated TRF2 in advanced breast cancers with short telomeres.	Diehl MC et al
19783902	2009	Sp1 upregulates expression of TRF2 and TRF2 inhibition reduces tumorigenesis in human colorectal carcinoma cells.	Dong W et al
22086963	2012	Ensembl 2012.	Flicek P et al
18077053	2008	Telomere shortening is associated with poor prognosis and telomerase activity correlates with DNA repair impairment in non-small cell lung cancer.	Frías C et al
22536324	2012	TRF2 controls telomeric nucleosome organization in a cell cycle phase-dependent manner.	Galati A et al
19854944	2010	The NCBI BioSystems database.	Geer LY et al
19285750	2009	Genetic variation in telomere maintenance genes, telomere length, and lung cancer susceptibility.	Hosgood HD 3rd et al
17643074	2007	Telomere attrition and chromosome instability via downregulation of TRF2 contributes to arsenic trioxide-induced apoptosis of human T-Cell leukemia cell line molt-4 cells.	Jiao Y et al
21558813	2011	Cell cycle-regulated association between the Werner syndrome protein and its molecular partners.	Jog SP et al
14741354	2004	TRF2 is in neuroglial cytoplasm and induces neurite-like processes.	Jung Y et al
19287395	2009	TRF2 functions as a protein hub and regulates telomere maintenance by recognizing specific peptide motifs.	Kim H et al
20404006	2010	Telomere maintenance and DNA damage responses during lung carcinogenesis.	Lantuejoul S et al
18212065	2008	WRN controls formation of extrachromosomal telomeric circles and is required for TRF2DeltaB-mediated telomere shortening.	Li B et al
15383534	2004	Telosome, a mammalian telomere-associated complex formed by multiple telomeric proteins.	Liu D et al
23387887	2012	Telomere shortening is a sole mechanism of aging in mammals.	Mikhelson VM et al
19756717	2010	Telomere biology in healthy aging and disease.	Oeseburg H et al
20929869	2011	genenames.org: the HGNC resources in 2011.	Seal RL et al
14967955	2003	Expression of a testis-specific form of TBP-related factor 2 (TRF2) mRNA during mouse spermatogenesis.	Sugiura S et al
21139605	2010	Towards a knowledge-based Human Protein Atlas.	Uhlen M et al
15507207	2004	Homologous recombination generates T-loop-sized deletions at human telomeres.	Wang RC et al
20655466	2010	TRF2 and apollo cooperate with topoisomerase 2alpha to protect human telomeres from replicative damage.	Ye J et al
21665207	2011	Genetic variants of 11 telomere-pathway gene loci and the risk of incident type 2 diabetes mellitus: the Women's Genome Health Study.	Zee RY et al
16166375	2005	Shelterin: the protein complex that shapes and safeguards human telomeres.	de Lange T et al
9476899	1998	TRF2 protects human telomeres from end-to-end fusions.	van Steensel B et al

Other Information

Locus ID:

NCBI: 7014
MIM: 602027
HGNC: 11729
Ensembl: ENSG00000132604

Variants:

dbSNP: 7014
ClinVar: 7014
TCGA: ENSG00000132604
COSMIC: TERF2

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000132604	ENST00000254942	Q15554
ENSG00000132604	ENST00000564982	J3KSJ9
ENSG00000132604	ENST00000566051	J3KTN8
ENSG00000132604	ENST00000566257	H3BTA7
ENSG00000132604	ENST00000566750	H3BR06
ENSG00000132604	ENST00000567296	Q15554
ENSG00000132604	ENST00000567841	V9GYM1
ENSG00000132604	ENST00000569280	H3BR37
ENSG00000132604	ENST00000569542	J3KSZ6
ENSG00000132604	ENST00000569584	U3KQ35

Expression (GTEx)

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
Shelterin complex	KEGG	hsa_M00424
Shelterin complex	KEGG	M00424
Cell Cycle	REACTOME	R-HSA-1640170
Chromosome Maintenance	REACTOME	R-HSA-73886
Telomere Maintenance	REACTOME	R-HSA-157579
Packaging Of Telomere Ends	REACTOME	R-HSA-171306
Meiosis	REACTOME	R-HSA-1500620
Meiotic synapsis	REACTOME	R-HSA-1221632
Cellular responses to stress	REACTOME	R-HSA-2262752
Cellular Senescence	REACTOME	R-HSA-2559583
DNA Damage/Telomere Stress Induced Senescence	REACTOME	R-HSA-2559586

Protein levels (Protein atlas)

Not detected

Low

Medium

High

References

Pubmed ID	Year	Title	Citations
38177309	2024	The shelterin component TRF2 mediates columnar stacking of human telomeric chromatin.	0
38323741	2024	The novel TERF2::PDGFRB fusion gene enhances tumorigenesis via PDGFRB/STAT5 signalling pathways and sensitivity to TKI in ph-like ALL.	0
38414350	2024	miR-29b-1-5p exacerbates myocardial injury induced by sepsis in a mouse model by targeting TERF2.	0
38177309	2024	The shelterin component TRF2 mediates columnar stacking of human telomeric chromatin.	0
38323741	2024	The novel TERF2::PDGFRB fusion gene enhances tumorigenesis via PDGFRB/STAT5 signalling pathways and sensitivity to TKI in ph-like ALL.	0
38414350	2024	miR-29b-1-5p exacerbates myocardial injury induced by sepsis in a mouse model by targeting TERF2.	0
36310382	2023	The telomeric protein TERF2/TRF2 impairs HMGB1-driven autophagy.	7
36651296	2023	Phosphorylation of TRF2 promotes its interaction with TIN2 and regulates DNA damage response at telomeres.	3
36719921	2023	TRF2 rescues telomere attrition and prolongs cell survival in Duchenne muscular dystrophy cardiomyocytes derived from human iPSCs.	4
36310382	2023	The telomeric protein TERF2/TRF2 impairs HMGB1-driven autophagy.	7
36651296	2023	Phosphorylation of TRF2 promotes its interaction with TIN2 and regulates DNA damage response at telomeres.	3
36719921	2023	TRF2 rescues telomere attrition and prolongs cell survival in Duchenne muscular dystrophy cardiomyocytes derived from human iPSCs.	4
35077681	2022	Compartmentalization of telomeres through DNA-scaffolded phase separation.	29
35240232	2022	TRF2 cooperates with CTCF for controlling the oncomiR-193b-3p in colorectal cancer.	8
35660868	2022	TRF2 inhibition rather than telomerase disruption drives CD4T cell dysfunction during chronic viral infection.	4

Citation

Molly L Bristol ; Claire P Bailey ; Lynne W Elmore

TERF2 (telomeric repeat binding factor 2)

Atlas Genet Cytogenet Oncol Haematol. 2013-02-01

Online version: http://atlasgeneticsoncology.org/gene/42522