# TERF2

## Overview
TERF2, also known as telomeric repeat binding factor 2, is a gene that encodes a protein integral to telomere maintenance and protection. The TERF2 protein is a key component of the shelterin complex, which safeguards chromosome ends by binding specifically to double-stranded telomeric DNA. This binding prevents the activation of DNA damage responses that could otherwise lead to inappropriate repair activities. The protein is characterized by its Myb-like DNA-binding domain, which facilitates its localization to telomeres, and a TRF-specific homology (TRFH) domain that enables dimerization, essential for its function in stabilizing telomeric structures (van1998TRF2; Hartmann2005Characterization). TERF2 plays a crucial role in the formation of t-loops, structures that protect chromosome ends from degradation and fusion, thereby ensuring genomic stability (Griffith1999Mammalian). Beyond its telomeric functions, TERF2 is implicated in broader chromatin organization and gene regulation, suggesting its involvement in diverse genomic processes (Simonet2011The).

## Structure
TERF2, also known as TRF2, is a protein involved in telomere maintenance and protection. The protein is composed of several distinct domains that contribute to its function. It contains a basic N-terminal domain, a central TRF-specific homology (TRFH) domain, and a C-terminal Myb-like DNA-binding domain (van1998TRF2; Hartmann2005Characterization). The TRFH domain is crucial for dimerization, allowing TERF2 to form homodimers, which is essential for its role in stabilizing telomeric structures (Hartmann2005Characterization; Kuimov2004Polypeptide).

The Myb-like domain at the C-terminus is responsible for binding to telomeric DNA, specifically the TTAGGG repeats, and is critical for the localization of TERF2 to telomeres (van1998TRF2; Hartmann2005Characterization). This domain is also involved in the formation of t-loops, which are large duplex loops that protect chromosome ends (Griffith1999Mammalian).

TERF2 undergoes alternative splicing, resulting in two isoforms with molecular masses of 65 and 69 kD (Kuimov2004Polypeptide). Post-translational modifications, such as phosphorylation, can influence TERF2's function and interactions, although specific details on these modifications are not extensively covered in the provided context.

## Function
TERF2, also known as TRF2, is a critical component of the shelterin complex, which is essential for maintaining telomere integrity in human cells. It specifically binds to double-stranded telomeric DNA, playing a pivotal role in protecting chromosome ends from being recognized as DNA double-strand breaks, thereby preventing inappropriate DNA damage responses and repair activities (Diala2013Telomere; Ye2010TRF2). TERF2 is involved in the formation of t loops, structures that protect chromosome ends from degradation and repair, ensuring chromosome stability (Ye2010TRF2).

TERF2 also regulates the activity of the exonuclease Apollo, which is crucial for telomere integrity during the S phase of the cell cycle. This regulation helps prevent telomere fusions and maintains proper telomere replication (Ye2010TRF2). Additionally, TERF2 acts as a sensor for topological stress during telomere replication, preferentially binding to positively supercoiled DNA, which helps manage topological problems that arise during the replication fork (Ye2010TRF2).

Beyond telomeres, TERF2 binds to interstitial telomeric sequences and other non-telomeric regions, suggesting a broader role in chromatin organization and gene regulation (Simonet2011The). This binding may influence gene expression and chromatin structure, potentially linking telomere function to broader genomic regulatory networks (Simonet2011The).

## Clinical Significance
Mutations and alterations in the expression of the TERF2 gene, also known as TRF2, have significant clinical implications, particularly in cancer. Abnormal TRF2 expression can lead to chromosomal instability (CIN), a hallmark of cancer, by causing errors in chromosome separation during mitosis, which can result in mutations such as polyploidy or aneuploidy (Wang2021Abnormal). In various cancers, including breast, stomach, and hematological malignancies, TRF2 expression is often reduced, contributing to cancer progression (Wang2021Abnormal). Conversely, increased TRF2 expression in certain tumors, such as gastric and liver cancers, is associated with immune evasion and drug resistance, making it a potential target for cancer therapy (Wang2021Abnormal).

In multiple myeloma, TERF2 shows high sensitivity and specificity as a biomarker for disease progression, with increased expression correlating with disease severity (Kumar2017Identifying). TRF2's role in maintaining telomere integrity is crucial for the proliferation and survival of cancer stem cells, contributing to tumor growth and resistance to treatments (Wang2021Abnormal). These findings highlight the potential of targeting TRF2 in therapeutic strategies to overcome drug resistance and enhance the effectiveness of existing cancer treatments (Wang2021Abnormal).

## Interactions
TERF2, also known as telomeric repeat binding factor 2, is a key component of the shelterin complex, which plays a crucial role in telomere protection and maintenance. TERF2 interacts with several proteins and nucleic acids to fulfill its functions. It directly binds to telomeric DNA through its Myb/SANT domain, which is essential for recognizing the double-stranded TTAGGG repeat sequence (Wang2021Abnormal).

TERF2 interacts with RTEL1, a helicase involved in dismantling t-loops during the S phase, to facilitate telomere maintenance. This interaction is mediated by the TRFH domain of TERF2, specifically between amino acids 106-125, with isoleucine 121 being critical for binding (Sarek2015TRF2). The interaction is essential for t-loop disassembly and is disrupted by specific mutations in either protein (Sarek2015TRF2).

TERF2 also forms a heterodimer with RAP1, another shelterin component, to protect telomeres from homologous recombination-mediated deletions and fusions. This interaction is crucial for repressing the localization of proteins like PARP1 and SLX4 to telomeres, thereby preventing telomere resection and chromosome fusions (Rai2016TRF2RAP1).

Additionally, TERF2 interacts with the Ku70/80 complex to inhibit canonical non-homologous end joining (C-NHEJ) at telomeres, maintaining telomere integrity by preventing chromosome end-to-end fusions (Wang2021Abnormal). These interactions highlight TERF2's multifaceted role in telomere biology and genome stability.


## References


[1. (van1998TRF2) Bas van Steensel, Agata Smogorzewska, and Titia de Lange. Trf2 protects human telomeres from end-to-end fusions. Cell, 92(3):401–413, February 1998. URL: http://dx.doi.org/10.1016/s0092-8674(00)80932-0, doi:10.1016/s0092-8674(00)80932-0. This article has 1342 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1016/s0092-8674(00)80932-0)

[2. (Simonet2011The) Thomas Simonet, Laure-Emmanuelle Zaragosi, Claude Philippe, Kevin Lebrigand, Clémentine Schouteden, Adeline Augereau, Serge Bauwens, Jing Ye, Marco Santagostino, Elena Giulotto, Frederique Magdinier, Béatrice Horard, Pascal Barbry, Rainer Waldmann, and Eric Gilson. The human ttaggg repeat factors 1 and 2 bind to a subset of interstitial telomeric sequences and satellite repeats. Cell Research, 21(7):1028–1038, March 2011. URL: http://dx.doi.org/10.1038/cr.2011.40, doi:10.1038/cr.2011.40. This article has 125 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1038/cr.2011.40)

[3. (Diala2013Telomere) Irmina Diala, Nicole Wagner, Frédérique Magdinier, Marina Shkreli, Maria Sirakov, Serge Bauwens, Caroline Schluth‐Bolard, Thomas Simonet, Valérie M Renault, Jing Ye, Abdelnnadir Djerbi, Pascal Pineau, Jinkuk Choi, Steven Artandi, Anne Dejean, Michelina Plateroti, and Eric Gilson. Telomere protection and trf2 expression are enhanced by the canonical wnt signalling pathway. EMBO reports, 14(4):356–363, February 2013. URL: http://dx.doi.org/10.1038/embor.2013.16, doi:10.1038/embor.2013.16. This article has 63 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1038/embor.2013.16)

[4. (Kuimov2004Polypeptide) A. N. Kuimov. Polypeptide components of telomere nucleoprotein complex. Biochemistry (Moscow), 69(2):117–129, February 2004. URL: http://dx.doi.org/10.1023/B:BIRY.0000018941.81962.1c, doi:10.1023/b:biry.0000018941.81962.1c. This article has 32 citations.](https://doi.org/10.1023/B:BIRY.0000018941.81962.1c)

[5. (Ye2010TRF2) Jing Ye, Christelle Lenain, Serge Bauwens, Angela Rizzo, Adelaïde Saint-Léger, Anaïs Poulet, Delphine Benarroch, Frédérique Magdinier, Julia Morere, Simon Amiard, Els Verhoeyen, Sébastien Britton, Patrick Calsou, Bernard Salles, Anna Bizard, Marc Nadal, Erica Salvati, Laure Sabatier, Yunlin Wu, Annamaria Biroccio, Arturo Londoño-Vallejo, Marie-Josèphe Giraud-Panis, and Eric Gilson. Trf2 and apollo cooperate with topoisomerase 2α to protect human telomeres from replicative damage. Cell, 142(2):230–242, July 2010. URL: http://dx.doi.org/10.1016/j.cell.2010.05.032, doi:10.1016/j.cell.2010.05.032. This article has 205 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1016/j.cell.2010.05.032)

[6. (Wang2021Abnormal) Zhengyi Wang and Xiaoying Wu. Abnormal function of telomere protein trf2 induces cell mutation and the effects of environmental tumor‑promoting factors (review). Oncology Reports, July 2021. URL: http://dx.doi.org/10.3892/or.2021.8135, doi:10.3892/or.2021.8135. This article has 15 citations and is from a peer-reviewed journal.](https://doi.org/10.3892/or.2021.8135)

[7. (Rai2016TRF2RAP1) Rekha Rai, Yong Chen, Ming Lei, and Sandy Chang. Trf2-rap1 is required to protect telomeres from engaging in homologous recombination-mediated deletions and fusions. Nature Communications, March 2016. URL: http://dx.doi.org/10.1038/ncomms10881, doi:10.1038/ncomms10881. This article has 108 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1038/ncomms10881)

[8. (Kumar2017Identifying) Raman Kumar, Rehan Khan, Nidhi Gupta, Tulika Seth, Atul Sharma, Mani Kalaivani, and Alpana Sharma. Identifying the biomarker potential of telomerase activity and shelterin complex molecule, telomeric repeat binding factor 2 (terf2), in multiple myeloma. Leukemia & Lymphoma, 59(7):1677–1689, October 2017. URL: http://dx.doi.org/10.1080/10428194.2017.1387915, doi:10.1080/10428194.2017.1387915. This article has 12 citations.](https://doi.org/10.1080/10428194.2017.1387915)

[9. (Sarek2015TRF2) Grzegorz Sarek, Jean-Baptiste Vannier, Stephanie Panier, John H.J. Petrini, and Simon J. Boulton. Trf2 recruits rtel1 to telomeres in s phase to promote t-loop unwinding. Molecular Cell, 57(4):622–635, February 2015. URL: http://dx.doi.org/10.1016/j.molcel.2014.12.024, doi:10.1016/j.molcel.2014.12.024. This article has 135 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1016/j.molcel.2014.12.024)

[10. (Hartmann2005Characterization) Nils Hartmann and Harry Scherthan. Characterization of the telomere complex, terf1 and terf2 genes in muntjac species with fusion karyotypes. Experimental Cell Research, 306(1):64–74, May 2005. URL: http://dx.doi.org/10.1016/j.yexcr.2005.02.001, doi:10.1016/j.yexcr.2005.02.001. This article has 8 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.yexcr.2005.02.001)

[11. (Griffith1999Mammalian) Jack D Griffith, Laurey Comeau, Soraya Rosenfield, Rachel M Stansel, Alessandro Bianchi, Heidi Moss, and Titia de Lange. Mammalian telomeres end in a large duplex loop. Cell, 97(4):503–514, May 1999. URL: http://dx.doi.org/10.1016/s0092-8674(00)80760-6, doi:10.1016/s0092-8674(00)80760-6. This article has 1810 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1016/s0092-8674(00)80760-6)