Telomeric repeat-binding factor 2 (original) (raw)

From Wikipedia, the free encyclopedia

Protein

TERF2
Available structuresPDBOrtholog search: PDBe RCSB List of PDB id codes1H6P, 1VF9, 1VFC, 1W0U, 1XG1, 3BU8, 3BUA, 3K6G, 3SJM, 4M7C, 4RQI
Identifiers
Aliases TERF2, TRBF2, TRF2, telomeric repeat binding factor 2
External IDs OMIM: 602027; MGI: 1195972; HomoloGene: 4133; GeneCards: TERF2; OMA:TERF2 - orthologs
Gene location (Human)Chromosome 16 (human)Chr.Chromosome 16 (human)[1]Chromosome 16 (human)Genomic location for TERF2Genomic location for TERF2Band16q22.1Start69,355,567 bp[1]End69,408,571 bp[1]
Gene location (Mouse)Chromosome 8 (mouse)Chr.Chromosome 8 (mouse)[2]Chromosome 8 (mouse)Genomic location for TERF2Genomic location for TERF2Band8 D3|8 53.59 cMStart107,069,400 bp[2]End107,096,547 bp[2]
RNA expression patternBgeeHuman Mouse (ortholog)Top expressed inBrodmann area 46sural nerveventricular zoneganglionic eminencepostcentral gyrusepithelium of colonorbitofrontal cortextesticleprefrontal cortexgastrocnemius muscleTop expressed intail of embryogenital tubercleinternal carotid arteryexternal carotid arteryzygoteRostral migratory streamretinal pigment epitheliumciliary bodysecondary oocytethymusMore reference expression dataBioGPSMore reference expression data
Gene ontologyMolecular function DNA binding double-stranded telomeric DNA binding protein homodimerization activity telomeric DNA binding telomerase activity protein C-terminus binding protein binding G-rich strand telomeric DNA binding enzyme binding protein-containing complex binding DNA-binding transcription factor activity, RNA polymerase II-specific Cellular component nuclear telomere cap complex chromosome telomere Mre11 complex nucleus nucleoplasm nuclear body shelterin complex axon cytoplasm Biological process negative regulation of telomere single strand break repair regulation of telomere maintenance negative regulation of telomere maintenance via semi-conservative replication negative regulation of gene expression negative regulation of beta-galactosidase activity protein localization to chromosome, telomeric region cellular senescence negative regulation of telomere capping positive regulation of gene expression positive regulation of nitric-oxide synthase activity negative regulation of t-circle formation cell cycle telomeric loop formation negative regulation of cellular senescence telomere capping negative regulation of telomere maintenance via telomere lengthening negative regulation of exonuclease activity telomeric D-loop disassembly negative regulation of telomeric D-loop disassembly negative regulation of telomere maintenance via recombination telomere maintenance RNA-dependent DNA biosynthetic process negative regulation of telomere maintenance regulation of telomere maintenance via telomerase negative regulation of telomere maintenance via telomerase protection from non-homologous end joining at telomere regulation of transcription by RNA polymerase II anterograde axonal transport of messenger ribonucleoprotein complex Sources:Amigo / QuickGO
OrthologsSpeciesHuman MouseEntrez701421750EnsemblENSG00000132604ENSMUSG00000031921UniProtQ15554O35144RefSeq (mRNA)NM_005652NM_001083118NM_001286200NM_009353RefSeq (protein)NP_005643NP_001076587NP_001273129NP_033379NP_001357994NP_001357995NP_001357996Location (UCSC)Chr 16: 69.36 – 69.41 MbChr 8: 107.07 – 107.1 MbPubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Telomeric repeat-binding factor 2 is a protein that is present at telomeres throughout the cell cycle. It is also known as TERF2, TRF2, and TRBF2, and is encoded in humans by the TERF2 gene.[5] It is a component of the shelterin nucleoprotein complex and a second negative regulator of telomere length, playing a key role in the protective activity of telomeres. It was first reported in 1997 in the lab of Titia de Lange,[6] where a DNA sequence similar, but not identical, to TERF1 was discovered, with respect to the Myb-domain. De Lange isolated the new Myb-containing protein sequence and called it TERF2.

Structure and domains

[edit]

TERF2 has a similar structure to that of TERF1. Both proteins carry a C-terminus Myb motif and large TERF1-related dimerization domains near their N-terminus.[6] However, both proteins exist exclusively as homodimers and do not heterodimerize with each other, as proven by co-immunoprecipitation assay analysis.[6] Also, TERF2 has a basic N-terminus, differing from TERF1’s acidic N-terminus, and was found to be much more conserved, suggesting that the two proteins have distinct functions.[7]

There are 4 domain categories on the TERF2 protein that allow it to bind to both other proteins in the shelterin protein complex, and to specific types of DNA.

TERF homology domain

[edit]

The TERF Homology Domain (TRFH; InterPro: IPR013867) is an area that helps to promote homodimerization of TERF2 with itself. This results in the formation of a quaternary structure that is characteristic of this protein. This TRFH domain also allows TERF2 to bind to and act as a dock for many other types of proteins. The Apollo nuclease, a shelterin accessory factor, uses the TRFH domain as a dock. The recruitment of Apollo by TERF2 allows for telomeric ends formed by DNA synthesis to be processed. By doing so, the telomere ends are able to avoid ATM kinase activation through the creation of a terminal structure.[8] SLX4, which is important in DNA repair by acting as a scaffold for structure-specific DNA repair nucleases, also binds to the TRFH domain of TERF2.[9] The TRFH domain is responsible for other binding events, including RTEL1, and proteins that contain a TBD site.

The Myb domain (InterPro: IPR017930) acts by binding to double-stranded telomeric DNA. This region gets its name from a viral protein called Myb derived from the avian myeloblastosis virus. Specifically, the sequence that this Myb domain targets on the DNA is (GGTTAG/CCAATC)n.

Basic and hinge domains

[edit]

Two other domains also work to bind and influence the activity of proteins associated with the TERF2 protein. Both are unique to TERF2. The basic domain sits at the N-terminal, and has two main functions: the prevention of t-loop excision by XRCC3, and the inhibition of SLX4. The final domain of TERF2 is called the hinge domain (InterPro: IPR031902). This domain contains a motif for binding the shelterin protein TIN2, which acts as a stabilizing protein, connecting units that are attached to double stranded and single stranded DNA.[10] This domain also is responsible for binding to RAP1, and helps to inhibit RNF168 recruitment at telomeres.

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.[7]

Specific domains on the TERF2 protein sequence and their functionalities.[11]

Telomeric ends are structurally similar to double-stranded breaks on the chromosome. To prevent the cellular DNA repair machinery from mistakenly identifying telomeres as chromosome breaks, t-loops are formed in which the 3’ TTAGGG overhang of the telomere loops back into the DNA duplex. TERF2 promotes t-loop formation by preferentially binding to a telomeric double-stranded DNA duplex containing a 3’ TTAGGG single-stranded overhang. If the 3’ TTAGGG overhang is not present, TERF2 will not bind. Once bound, it migrates to the t-loop junction where the single-stranded overhang invades the double-stranded region upstream. No other shelterin protein has been shown to promote this process but interaction of TERF2 with TERF2IP is shown to promote higher t-loop formation in vitro.[12] Studies have demonstrated that deletion of TERF2 prevents t-loop formation, leading to excessive loss of telomeric DNA and early cell death.[13]

ATM kinase prevention

[edit]

TERF2 plays a central role in preventing ATM kinase DNA damage response. It binds telomeric dsDNA and prevents telomeres from activating ATM kinase. This interaction of TERF2 with ATM is believed to be relevant to the mechanism by which TERF2 blocks ATM signaling. Because of its oligomeric nature, TERF2 could potentially cross-link ATM monomers and hold the kinase in its inactive dimeric state, thereby blocking amplification of the ATM signal at an early step in its activation. However, because mutations in the TERF2 dimerization domain destabilize the protein, it has not been possible to test the contribution of TERF2 oligomerization on ATM repression directly. Removal of TERF2 induces ATM-dependent apoptosis by localizing the active, phosphorylated form of ATM to unprotected chromosome ends. Since TERF2 specifically binds at telomeres and remains there when DNA damage is induced, it is unlikely to interfere with activation of the ATM kinase at different sites of DNA damage. Therefore, TERF2 could act as a telomere-specific inhibitor of ATM kinase.[14]

TERF2 Knockout Effects

[edit]

Conditional deletion of TERF2 in mice cells effectively removes the shelterin nucleoprotein complex. As a result of removing this complex, several unwanted DNA damage response pathways are activated, including ATM kinase signaling, ATR kinase signaling, non-homologous end-joining (NHEJ), alt-NHEJ, C-NHEJ, 5' resection, and homology directed repair (HDR).[15] These repair pathways (in the presence of P53 knockout and Cre) often contribute to the phenotype where chromosome ends are connected to each other in a very long chain, which can be visualized by a combination of a DAPI stain and fluorescence in situ hybridization (FISH) technique.

Client proteins have a distinctive YxLxP motif (where "x" can be any amino acid) that bind to TERF2.[16]

TERF2 is also known to recruit certain client proteins, also known as accessory factors. These client proteins are often recruited to TERF2 for a specific function at a specific time, often temporarily. The TRFH domain contains a F120 residue, which is the binding site of TERF2 where it recruits client proteins. These client proteins also contain a TRFH binding motif, which consists of a conserved 6-amino acid sequence of the following formula: YxLxP, where "x" can be any amino acid substituted.[16] The above-mentioned Apollo nuclease (one of many TERF2's client proteins) also contains the formulaic motif; its specific motif sequence is YLLTP.

TERF1 also demonstrates similar client protein recruitment mechanism as TERF2, except that it diverges at two concepts: 1) the TRFH of TERF1 contains a F142 residue, 2) the client proteins specific for TERF1 contain the TRFH binding motif sequence of FxLxP, where the amino acid Y (tyrosine) is replaced with F (phenylalanine).

TERF2 has also been shown to interact with:

Disease relevance of TERF2

[edit]

Telomerase is an enzyme that works to create telomeric ends for DNA, and it is thought to play important roles in the development of cancer. Specifically, telomeric stability is known to be a common occurrence in cancer cells.[23] Along with the telomerase, the shelterin complex, and TERF2 and TERF1 specifically, also have been noted to control the lengths of telomeres formed by these telomerases. Shelterin works to protect telomeres against unsuitable activation of the DNA damage response pathway, as noted in the function section above. TERF2 as part of the shelterin complex, has been known to block the ATM signaling pathways and prevent chromosome end fusion. In cancer cells, TERF2 phosphorylation by extracellular signal-regulated kinase (ERK1/2) is a controlling factor in the major pro-oncogenic signaling pathways (RAS/RAF/MEK/ERK) that affect telomeric stability.[23] Additionally, when TERF2 was non-phosphorylated in melanoma cells, there was a cell induced DNA damage response, arresting growth and causing tumor reversion.[23] Studies have found that in tumor cells, TERF2 levels are observed to be high, and this raised level of TERF2 contributes to oncogenesis in a variety of ways.[24][25][26] This high level of TERF2 decreases the ability to recruit and activate natural killer cells in human tumor cells.[24] One study used a dominant negative form of TERF2ΔBΔC, to inhibit TERF2, and found that it could induce a reversion malignant phenotype in human melanoma cells.[25] Therefore, over-expression of TERF2ΔBΔC, causing blocking of TERF2, induced apoptosis and reduced tumourigenicity in certain cell lines.[25] Additionally, upregulation of TERF2 may be the cause of the establishment and maintenance of short telomeres.[26] These short telomeres increase chromosomal instability, and increase the chances of certain cancers progressing in the body, such as with leukemia.[26] In gastric mucosa tissues, the expression of TERF2 proteins was significantly higher than normal, and this over-expression of TERF2, along with over-expression of TERF1, TIN2, TERT, and BRCA1 protein transposition, may cause a reduction in telomere length, further contributing to multistage carcinogenesis of gastric cancer.[27]

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000132604 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000031921 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Sakaguchi AY, Padalecki SS, Mattern V, Rodriguez A, Leach RJ, McGill JR, Chavez M, Giambernardi TA (May 1998). "Chromosomal sublocalization of the transcribed human telomere repeat binding factor 2 gene and comparative mapping in the mouse". Somat. Cell Mol. Genet. 24 (3): 157–63. doi:10.1023/b:scam.0000007118.47691.d7. PMID 10226653. S2CID 26610531.
  6. ^ a b c Broccoli D, Smogorzewska A, Chong L, de Lange T (October 1997). "Human telomeres contain two distinct Myb-related proteins, TRF1 and TRF2". Nature Genetics. 17 (2): 231–5. doi:10.1038/ng1097-231. PMID 9326950. S2CID 41204064.
  7. ^ a b "Entrez Gene: TERF2 telomeric repeat binding factor 2".
  8. ^ Wu P, van Overbeek M, Rooney S, de Lange T (August 2010). "Apollo contributes to G overhang maintenance and protects leading-end telomeres". Molecular Cell. 39 (4): 606–17. doi:10.1016/j.molcel.2010.06.031. PMC 2929323. PMID 20619712.
  9. ^ Wilson JS, Tejera AM, Castor D, Toth R, Blasco MA, Rouse J (September 2013). "Localization-dependent and -independent roles of SLX4 in regulating telomeres". Cell Reports. 4 (5): 853–60. doi:10.1016/j.celrep.2013.07.033. PMC 3969258. PMID 23994477.
  10. ^ Palm W, de Lange T (2008-11-04). "How shelterin protects mammalian telomeres". Annual Review of Genetics. 42 (1): 301–34. doi:10.1146/annurev.genet.41.110306.130350. PMID 18680434.
  11. ^ Arnoult N, Karlseder J (November 2015). "Complex interactions between the DNA-damage response and mammalian telomeres". Nature Structural & Molecular Biology. 22 (11): 859–66. doi:10.1038/nsmb.3092. PMC 4739752. PMID 26581520.
  12. ^ Arat NÖ, Griffith JD (December 2012). "Human Rap1 interacts directly with telomeric DNA and regulates TRF2 localization at the telomere". The Journal of Biological Chemistry. 287 (50): 41583–94. doi:10.1074/jbc.M112.415984. PMC 3516710. PMID 23086976.
  13. ^ Stansel RM, de Lange T, Griffith JD (October 2001). "T-loop assembly in vitro involves binding of TRF2 near the 3' telomeric overhang". The EMBO Journal. 20 (19): 5532–40. doi:10.1093/emboj/20.19.5532. PMC 125642. PMID 11574485.
  14. ^ Karlseder J, Hoke K, Mirzoeva OK, Bakkenist C, Kastan MB, Petrini JH, de Lange T (August 2004). "The telomeric protein TRF2 binds the ATM kinase and can inhibit the ATM-dependent DNA damage response". PLOS Biology. 2 (8): E240. doi:10.1371/journal.pbio.0020240. PMC 509302. PMID 15314656.
  15. ^ Sfeir A, de Lange T (May 2012). "Removal of shelterin reveals the telomere end-protection problem". Science. 336 (6081): 593–7. Bibcode:2012Sci...336..593S. doi:10.1126/science.1218498. PMC 3477646. PMID 22556254.
  16. ^ a b Chen Y, Yang Y, van Overbeek M, Donigian JR, Baciu P, de Lange T, Lei M (February 2008). "A shared docking motif in TRF1 and TRF2 used for differential recruitment of telomeric proteins". Science. 319 (5866): 1092–6. Bibcode:2008Sci...319.1092C. doi:10.1126/science.1151804. PMID 18202258. S2CID 54523266.
  17. ^ Song K, Jung D, Jung Y, Lee SG, Lee I (September 2000). "Interaction of human Ku70 with TRF2". FEBS Letters. 481 (1): 81–5. doi:10.1016/s0014-5793(00)01958-x. PMID 10984620. S2CID 22753893.
  18. ^ a b c d Zhu XD, Küster B, Mann M, Petrini JH, de Lange T (July 2000). "Cell-cycle-regulated association of RAD50/MRE11/NBS1 with TRF2 and human telomeres". Nature Genetics. 25 (3): 347–52. doi:10.1038/77139. PMID 10888888. S2CID 6689794.
  19. ^ a b O'Connor MS, Safari A, Liu D, Qin J, Songyang Z (July 2004). "The human Rap1 protein complex and modulation of telomere length". The Journal of Biological Chemistry. 279 (27): 28585–91. doi:10.1074/jbc.M312913200. PMID 15100233.
  20. ^ Zhang P, Casaday-Potts R, Precht P, Jiang H, Liu Y, Pazin MJ, Mattson MP (September 2011). "Nontelomeric splice variant of telomere repeat-binding factor 2 maintains neuronal traits by sequestering repressor element 1-silencing transcription factor". Proceedings of the National Academy of Sciences of the United States of America. 108 (39): 16434–9. Bibcode:2011PNAS..10816434Z. doi:10.1073/pnas.1106906108. PMC 3182730. PMID 21903926.
  21. ^ Li B, Oestreich S, de Lange T (May 2000). "Identification of human Rap1: implications for telomere evolution". Cell. 101 (5): 471–83. doi:10.1016/S0092-8674(00)80858-2. PMID 10850490. S2CID 7956545.
  22. ^ Opresko PL, von Kobbe C, Laine JP, Harrigan J, Hickson ID, Bohr VA (October 2002). "Telomere-binding protein TRF2 binds to and stimulates the Werner and Bloom syndrome helicases". The Journal of Biological Chemistry. 277 (43): 41110–9. doi:10.1074/jbc.M205396200. PMID 12181313.
  23. ^ a b c Picco V, Coste I, Giraud-Panis MJ, Renno T, Gilson E, Pagès G (July 2016). "ERK1/2/MAPK pathway-dependent regulation of the telomeric factor TRF2". Oncotarget. 7 (29): 46615–46627. doi:10.18632/oncotarget.10316. PMC 5216822. PMID 27366950.
  24. ^ a b Biroccio A, Cherfils-Vicini J, Augereau A, Pinte S, Bauwens S, Ye J, Simonet T, Horard B, Jamet K, Cervera L, Mendez-Bermudez A, Poncet D, Grataroli R, de Rodenbeeke CT, Salvati E, Rizzo A, Zizza P, Ricoul M, Cognet C, Kuilman T, Duret H, Lépinasse F, Marvel J, Verhoeyen E, Cosset FL, Peeper D, Smyth MJ, Londoño-Vallejo A, Sabatier L, Picco V, Pages G, Scoazec JY, Stoppacciaro A, Leonetti C, Vivier E, Gilson E (July 2013). "TRF2 inhibits a cell-extrinsic pathway through which natural killer cells eliminate cancer cells". Nature Cell Biology. 15 (7): 818–28. doi:10.1038/ncb2774. hdl:11573/559592. PMID 23792691. S2CID 205287459.
  25. ^ a b c Biroccio A, Rizzo A, Elli R, Koering CE, Belleville A, Benassi B, Leonetti C, Stevens MF, D'Incalci M, Zupi G, Gilson E (August 2006). "TRF2 inhibition triggers apoptosis and reduces tumourigenicity of human melanoma cells". European Journal of Cancer. 42 (12): 1881–8. doi:10.1016/j.ejca.2006.03.010. PMID 16750909.
  26. ^ a b c Bellon M, Datta A, Brown M, Pouliquen JF, Couppie P, Kazanji M, Nicot C (November 2006). "Increased expression of telomere length regulating factors TRF1, TRF2 and TIN2 in patients with adult T-cell leukemia". International Journal of Cancer. 119 (9): 2090–7. doi:10.1002/ijc.22026. PMID 16786598. S2CID 37883075.
  27. ^ Hu H, Zhang Y, Zou M, Yang S, Liang XQ (September 2010). "Expression of TRF1, TRF2, TIN2, TERT, KU70, and BRCA1 proteins is associated with telomere shortening and may contribute to multistage carcinogenesis of gastric cancer". Journal of Cancer Research and Clinical Oncology. 136 (9): 1407–14. doi:10.1007/s00432-010-0795-x. PMID 20127252. S2CID 19253770.