TERF2 (telomeric repeat binding factor 2)

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

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




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


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


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).


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


Atlas Image
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.


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).


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).


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).


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).


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).



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


Pubmed IDLast YearTitleAuthors
184222782008[Expression of telomere binding factor 2 (TRF2) on leukemia cell lines and primary leukemia cells].Chen XH et al
191428872009Telomere-associated proteins: cross-talk between telomere maintenance and telomere-lengthening mechanisms.De Boeck G et al
206258122011Elevated TRF2 in advanced breast cancers with short telomeres.Diehl MC et al
197839022009Sp1 upregulates expression of TRF2 and TRF2 inhibition reduces tumorigenesis in human colorectal carcinoma cells.Dong W et al
220869632012Ensembl 2012.Flicek P et al
180770532008Telomere shortening is associated with poor prognosis and telomerase activity correlates with DNA repair impairment in non-small cell lung cancer.Frías C et al
225363242012TRF2 controls telomeric nucleosome organization in a cell cycle phase-dependent manner.Galati A et al
198549442010The NCBI BioSystems database.Geer LY et al
192857502009Genetic variation in telomere maintenance genes, telomere length, and lung cancer susceptibility.Hosgood HD 3rd et al
176430742007Telomere 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
215588132011Cell cycle-regulated association between the Werner syndrome protein and its molecular partners.Jog SP et al
147413542004TRF2 is in neuroglial cytoplasm and induces neurite-like processes.Jung Y et al
192873952009TRF2 functions as a protein hub and regulates telomere maintenance by recognizing specific peptide motifs.Kim H et al
204040062010Telomere maintenance and DNA damage responses during lung carcinogenesis.Lantuejoul S et al
182120652008WRN controls formation of extrachromosomal telomeric circles and is required for TRF2DeltaB-mediated telomere shortening.Li B et al
153835342004Telosome, a mammalian telomere-associated complex formed by multiple telomeric proteins.Liu D et al
233878872012Telomere shortening is a sole mechanism of aging in mammals.Mikhelson VM et al
197567172010Telomere biology in healthy aging and disease.Oeseburg H et al
209298692011genenames.org: the HGNC resources in 2011.Seal RL et al
149679552003Expression of a testis-specific form of TBP-related factor 2 (TRF2) mRNA during mouse spermatogenesis.Sugiura S et al
211396052010Towards a knowledge-based Human Protein Atlas.Uhlen M et al
155072072004Homologous recombination generates T-loop-sized deletions at human telomeres.Wang RC et al
206554662010TRF2 and apollo cooperate with topoisomerase 2alpha to protect human telomeres from replicative damage.Ye J et al
216652072011Genetic 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
161663752005Shelterin: the protein complex that shapes and safeguards human telomeres.de Lange T et al
94768991998TRF2 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


dbSNP: 7014
ClinVar: 7014
TCGA: ENSG00000132604


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Shelterin complexKEGGhsa_M00424
Shelterin complexKEGGM00424
Cell CycleREACTOMER-HSA-1640170
Chromosome MaintenanceREACTOMER-HSA-73886
Telomere MaintenanceREACTOMER-HSA-157579
Packaging Of Telomere EndsREACTOMER-HSA-171306
Meiotic synapsisREACTOMER-HSA-1221632
Cellular responses to stressREACTOMER-HSA-2262752
Cellular SenescenceREACTOMER-HSA-2559583
DNA Damage/Telomere Stress Induced SenescenceREACTOMER-HSA-2559586

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
119235372002Senescence induced by altered telomere state, not telomere loss.212
197167862009TERRA RNA binding to TRF2 facilitates heterochromatin formation and ORC recruitment at telomeres.192
121813132002Telomere-binding protein TRF2 binds to and stimulates the Werner and Bloom syndrome helicases.137
153160052004TIN2 binds TRF1 and TRF2 simultaneously and stabilizes the TRF2 complex on telomeres.121
153146562004The telomeric protein TRF2 binds the ATM kinase and can inhibit the ATM-dependent DNA damage response.120
182022582008A shared docking motif in TRF1 and TRF2 used for differential recruitment of telomeric proteins.116
115772372001Strand-specific postreplicative processing of mammalian telomeres.94
168803782006A critical role for TPP1 and TIN2 interaction in high-order telomeric complex assembly.94
156086172005How the human telomeric proteins TRF1 and TRF2 recognize telomeric DNA: a view from high-resolution crystal structures.83
152922642004TIN2 mediates functions of TRF2 at human telomeres.79


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/terf2-(telomeric-repeat-binding-factor-2)