Alternative titles; symbols
HGNC Approved Gene Symbol: TERF2
Cytogenetic location: 16q22.1 Genomic coordinates (GRCh38): 16:69,355,567-69,386,007 (from NCBI)
Human telomeres are composed of long arrays of TTAGGG repeats that form a nucleoprotein complex required for the protection and replication of chromosome ends. One component of human telomeres is the TTAGGG repeat binding factor-1 (TRF1; 600951), a ubiquitously expressed protein related to the protooncogene Myb (189990), that is present at telomeres throughout the cell cycle. TRF1 is involved in the control of telomere lengths. It functions as an inhibitor of telomerase, acting in cis to limit the elongation of individual chromosome ends. Broccoli et al. (1997) reported the cloning of TRF2, a distant homolog of TRF1 that carries a very similar Myb-related DNA-binding motif (also called the 'telobox'). Like TRF1, TRF2 is ubiquitously expressed, bound specifically to duplex TTAGGG repeats in vitro, and localized to all human telomeres in metaphase chromosomes. TRF2 was shown to have an architecture similar to that of TRF1 in that it carries a C-terminal Myb motif and a large TRF1-related dimerization domain near its N terminus. However, the dimerization domains of TRF1 and TRF2 did not interact, suggesting that these proteins exist predominantly as homodimers. While having similar telomere binding activity and domain organization, TRF2 differs from TRF1 in that its N terminus is basic rather than acidic, and TRF2 is much more conserved than TRF1. Because of the differences between TRF1 and TRF2, Broccoli et al. (1997) suggested that these factors have distinct functions at the telomeres. Independently, Bilaud et al. (1997) identified a second human open reading frame containing a telobox sequence and encoding a polypeptide that specifically recognizes mammalian telomeric repeat DNA in vitro. They showed that 2 proteins of 65 and 69 kD, expressed in HeLa cells, contain this second telobox sequence. These proteins were collectively termed TRF2. Affinity-purified antibodies specific for anti-TRF2 labeled the telomeres of intact human chromosomes, strengthening the correlation between occurrence of telobox and telomere-repeat recognition in vivo.
Sakaguchi et al. (1998) mapped the TERF2 gene to chromosome 16q22.1 by analysis of a monochromosomal mapping panel and a radiation hybrid panel. The mouse Terf2 gene was localized to chromosome 8, to a large evolutionarily conserved linkage group of at least 25 genes.
Van Steensel et al. (1998) showed that the human telomeric protein TRF2 plays a key role in the protective activity of telomeres. A dominant-negative allele of TRF2 induced end-to-end chromosome fusions detectable in metaphase and anaphase cells. Telomeric DNA persisted at the fusions, demonstrating that TTAGGG repeats per se are not sufficient for telomere integrity. Molecular analysis suggested that the fusions represented ligation of telomeres that have lost their single-stranded G-tails. Van Steensel et al. (1998) concluded that TRF2 may protect chromosome ends by maintaining the correct structure at telomere termini. In addition, expression of mutant forms of TRF2 induced a growth arrest with characteristics of senescence. These results raise the possibility that chromosome end fusions and senescence in primary human cells may be caused by loss by TRF2 from shortened telomeres.
Using electron microscopy, Griffith et al. (1999) demonstrated that TRF2 can remodel linear telomeric DNA into large duplex loops (t loops) in vitro. Electron microscopy analysis of psoralen cross-linked telomeric DNA purified from human and mouse cells revealed abundant large t loops with a size distribution consistent with their telomeric origin. Binding of TRF1 and single-stranded DNA-binding protein (600439) suggested that t loops are formed by invasion of the 3-prime telomeric overhang into the duplex telomeric repeat array. Griffith et al. (1999) concluded that t loops may provide a general mechanism for the protection and replication of telomeres.
Telomeres allow cells to distinguish natural chromosome ends from damaged DNA and protect the ends from degradation and fusion. In human cells, telomere protection depends on the TTAGGG repeat-binding factor TRF2, which may remodel telomeres into t loops. Zhu et al. (2000) demonstrated cell cycle-regulated association of the RAD50/MRE11/NBS1 complex (see 604040) with TRF2 and human telomeres. Although the MRE11 complex accumulated in irradiation-induced foci (IRIFs) in response to gamma-irradiation, TRF2 did not relocate to IRIFs and irradiation did not affect the association of TRF2 with the MRE11 complex, arguing against a role for TRF2 in double-strand break repair. Zhu et al. (2000) proposed that the RAD50/MRE11/NBS1 complex functions at telomeres, possibly by modulating t loop formation.
In mammalian cells, abrogation of telomeric repeat binding factor TRF2 were DNA-dependent protein kinase (600899) activity causes end to end chromosomal fusion, thus establishing a central role for these proteins in telomere function. Bailey et al. (2001) demonstrated that TRF2-mediated end-capping occurs after telomere replication. The postreplicative requirement for TRF2 and DNA-PK catalytic subunit is confined to only half of the telomeres, namely, those that were produced by leading-strand DNA synthesis. Bailey et al. (2001) concluded that their results demonstrate a crucial difference in postreplicative processing of telomeres that is linked to their mode of replication.
Karlseder et al. (2002) reported that overexpression of TRF2 increased the rate of telomere shortening in primary cells without accelerating senescence. TRF2 reduced the senescence set point, defined as telomere length at senescence, from 7 to 4 kb. TRF2 protected critically short telomeres from fusion and repressed chromosome-end fusions in presenescent cultures, which explained the ability of TRF2 to delay senescence. Thus, Karlseder et al. (2002) concluded that replicative senescence is induced by a change in the protected status of shortened telomeres rather than by a complete loss of telomeric DNA.
Opresko et al. (2002) found that TRF2 colocalized and physically interacted with the RecQ DNA helicase, WRN (604611), and that the interaction was mediated by the RecQ conserved C-terminal region of WRN. In vitro, TRF2 showed high affinity for WRN and for a second RecQ DNA helicase, BLM (RECQL3; 604610). TRF2 interaction with either helicase resulted in stimulation of its activity. The WRN or BLM helicases, partnered with replication protein A (see 179835), actively unwound long telomeric duplex regions that were pre-bound by TRF2. Opresko et al. (2002) concluded that TRF2 functions with WRN, and possibly BLM, in a common pathway at the telomeric ends.
Telomerase-negative immortalized human cells maintain telomeres by alternative lengthening of telomeres (ALT) pathway(s), which may involve homologous recombination (Bryan et al., 1997). Stavropoulos et al. (2002) found that endogenous BLM protein colocalized with telomeric foci in ALT human cells but not telomerase-positive immortal cell lines or primary cells. BLM interacted in vivo with the telomeric protein TRF2 in ALT cells, as detected by FRET and coimmunoprecipitation. Transient overexpression of GFP-BLM resulted in marked, ALT cell-specific increases in telomeric DNA. The association of BLM with telomeres and its effect on telomere DNA synthesis required a functional helicase domain. The authors suggested that BLM may facilitate recombination-driven amplification of telomeres in ALT cells.
Wang et al. (2004) reported that a TRF2 mutant lacking the N-terminal basic domain, termed TRF2(delta-B), suppressed nonhomologous end joining but induced catastrophic deletions of telomeric DNA. The deletion events were stochastic and occurred rapidly, generating dramatically shortened telomeres that were accompanied by a DNA damage response and induction of senescence. TRF2(delta-B)-induced deletions depended on XRCC3 (600675), a protein implicated in Holliday junction resolution, and created t-loop-sized telomeric circles. These telomeric circles were also detected in unperturbed cells and suggested that t-loop deletion by homologous recombination might contribute to telomere attrition. Human ALT cells had abundant telomeric circles, pointing to frequent t-loop homologous recombination events that could promote rolling circle replication of telomeres in the absence of telomerase.
In addition to increased DNA strand exchange, another cytogenetic feature of Bloom syndrome (210900) cells lacking BLM is the tendency for telomeres to associate. Lillard-Wetherell et al. (2004) reported that BLM colocalized and complexed with TERF2 in cells that employ ALT. BLM colocalized with TERF2 in foci actively synthesizing DNA during late S and G2/M; colocalization increased in late S and G2/M when ALT is thought to occur. TERF1 (600951) and TERF2 interacted directly with BLM and regulated its unwinding activity in vitro. Whereas TERF2 stimulated BLM unwinding of telomeric and nontelomeric substrates, TERF1 inhibited its unwinding of telomeric substrates only. TERF2 stimulated BLM unwinding with equimolar concentrations of TERF1, but not when TERF1 was added in molar excess. Lillard-Wetherell et al. (2004) proposed a function for BLM in recombination-mediated telomere lengthening and a model for the coordinated regulation of BLM activity at telomeres by TERF1 and TERF2.
DNA damage surveillance networks in human cells can activate DNA repair, cell cycle checkpoints, and apoptosis in response to fewer than 4 double-strand breaks (DSBs) per genome. These same networks tolerate telomeres, in part because the protein TRF2 prevents recognition of telomeric ends as DSBs by facilitating their organization into t loops. Bradshaw et al. (2005) showed that TRF2 associates with photo-induced DSBs in nontelomeric DNA in human fibroblasts within 2 seconds of irradiation. These and other results implicated TRF2 in an initial stage of DSB recognition and processing that occurs before association of ATM (607585) with DSBs and activation of the ATM-dependent DSB response network.
Telomere repeats in the fission yeast Schizosaccharomyces pombe are bound by Taz1, a regulator of diverse telomere functions. Miller et al. (2006) showed that Taz1 is crucial for efficient replication fork progression through the telomere. Using 2-dimensional gel electrophoresis, Miller et al. (2006) found that loss of Taz1 leads to stalled replication forks at telomeres and internally placed telomere sequences, regardless of whether the telomeric G-rich strand is replicated by leading- or lagging-strand synthesis. In contrast, the Taz1-interacting protein Rap1 (605061) is dispensable for efficient telomeric fork progression. Upon loss of telomerase, Taz1-delta telomeres are lost precipitously, suggesting that maintenance of Taz1-delta telomere repeats cannot be sustained through semiconservative replication. As the human telomere proteins TRF1 and TRF2 are Taz1 orthologs, Miller et al. (2006) predicted that 1 or both of the human TRFs may orchestrate fork passage through human telomeres. Stalled forks at dysfunctional human telomeres are likely to accelerate the genomic instability that drives tumorigenesis.
Using yeast 2-hybrid and protein pull-down assays, Lenain et al. (2006) showed that the N terminus of human Apollo (DCLRE1B; 609683) bound TRF2 in a DNA-independent manner. TRF2 was required for Apollo telomeric localization.
Williams et al. (2007) observed the recruitment of fluorescence-tagged TERF2 to sites of DNA damage in HeLa cells caused by a high-intensity multiphoton laser beam in the presence of a photosensitizing dye, which is consistent with the results of Bradshaw et al. (2005). However, no recruitment of TERF2 to sites of DNA damage was elicited in human cells and cell lines caused by a more conventional laser beam, or by exposure to alpha particle irradiation or ultraviolet C light. Williams et al. (2007) concluded that DNA double-strand breaks are not sufficient to initiate recruitment of TRF2.
Mammalian telomeres are protected by a 6-protein complex, shelterin. Shelterin contains 2 closely related proteins, TRF1 (600951) and TRF2, which recruit various proteins to telomeres. Chen et al. (2008) dissected the interactions of TRF1 and TRF2 with their shared binding partner TIN2 (604319) and other shelterin accessory factors. TRF1 recognizes TIN2 using a conserved molecular surface in its TRF homology domain. However, this same surface does not act as a TIN2 binding site in TRF2, and TIN2 binding to TRF2 is mediated by a region outside the TRF homology domain. Instead, the TRF homology domain docking site of TRF2 binds a shelterin accessory factor, Apollo, which does not interact with the TRF homology domain of TRF1. Conversely, the TRF homology domain of TRF1, but not of TRF2, interacts with another shelterin-associated factor, PINX1 (606505).
Sfeir et al. (2010) removed Rap1 from mouse telomeres either through gene deletion or by replacing Trf2 with a mutant that does not bind Rap1. Rap1 was dispensable for essential functions of Trf2--repression of ATM kinase signaling and nonhomologous end-joining--and mice lacking telomeric Rap1 were viable and fertile. However, Rap1 was critical for the repression of homology-directed repair, which can alter telomere length. The data of Sfeir et al. (2010) revealed that homology-directed repair at telomeres can take place in the absence of DNA damage foci and underscored the functional compartmentalization within shelterin.
Ye et al. (2010) showed that TRF2 stimulated the exonuclease activity of Apollo against single-stranded telomeric DNA, but not against double-stranded substrates that mimicked telomeric DNA ends. Both proteins bound an 800-bp telomeric sequence artificially integrated into the middle of chromosome 4q. Telomere deficiencies due to inhibition or knockdown of TOP2-alpha (TOP2A; 126430) were rescued by overexpression of Apollo and TRF2. Overexpression of Apollo and TRF2 reduced the requirement for TOP2-alpha for telomere replication. Ye et al. (2010) found that TRF2 showed preferential binding to positively supercoiled DNA. They hypothesized that TRF2-Apollo and TOP2 act in concert to release positive superhelical strain created in telomeric DNA during replication fork progression.
To define the telomere end-protection problem, Sfeir and de Lange (2012) removed the whole shelterin complex from mouse telomeres through conditional deletion of TRF1 and TFR2 in nonhomologous end-joining (NHEJ)-deficient cells. The data revealed 2 DNA damage response pathways not theretofore observed upon deletion of individual shelterin proteins. The shelterin-free telomeres are processed by microhomology-mediated alternative-NHEJ when Ku70/80 (152690/194364) is absent and are attacked by nucleolytic degradation in the absence of 53BP1 (605230). Sfeir and de Lange (2012) concluded that their data established that the end-protection problem is specified by 6 pathways (ATM and ATR signaling, classical-NHEJ, alt-NHEJ, homologous recombination, and resection), and showed how shelterin acts with general DNA damage response factors to solve this problem.
Okamoto et al. (2013) addressed the molecular properties of TRF2 that are both necessary and sufficient to protect chromosome ends in mouse embryonic fibroblasts, and stated that their data supported a 2-step mechanism for TRF2-mediated end protection. First, the dimerization domain of TRF2 is required to inhibit ATM (607585) activation, the key initial step involved in the activation of a DNA damage response (DDR). Next, TRF2 independently suppresses the propagation of DNA damage signaling downstream of ATM activation. This novel modulation of the DDR at telomeres occurs at the level of the E3 ubiquitin ligase RNF168 (612688). Inhibition of RNF168 at telomeres involves the deubiquitinating enzyme BRCC3 (300617) and the ubiquitin ligase UBR5 (608413), and is sufficient to suppress chromosome end-to-end fusions. Okamoto et al. (2013) concluded that this 2-step mechanism for TRF2-mediated end protection helped to explain the apparent paradox of frequent localization of DDR proteins at functional telomeres without concurrent induction of detrimental DNA repair activities.
Grammatikakis et al. (2016) noted that, in rodents, alternative splicing produces a short Trf2 variant, Trf2s, that includes only part of exon 7. The Trf2s protein lacks the DNA-binding domain and nuclear localization signal of full-length Trf2 and instead possesses a short sequence that retains Trf2s in the cytoplasm. Trf2s has the ability to bind to and inactivate Rest (600571) in the cytoplasm, resulting in derepression of neuronal genes. Using a proteomic screen of rat cerebellar extracts, Grammatikakis et al. (2016) found that the RNA-binding proteins Hnrnph1 (601035) and Hnrnph2 (300610) interacted with exon 7 of Trf2 pre-mRNA. The HNRNPH proteins inhibited use of the 5-prime alternative splice site in exon 7, promoting inclusion of exon 7 and thereby increasing the relative levels of full-length Trf2 and lowering Trf2s abundance. HNRNPH protein levels decreased during neuronal differentiation, whereas Trf2s levels increased. CRISPR-mediated deletion of Hnrnph2 accelerated neuronal differentiation. Grammatikakis et al. (2016) concluded that HNRNPH1 and HNRNPH2 repress neuronal differentiation, at least in part, by inhibiting alternative splicing of TRF2.
Sarek et al. (2019) identified a CDK phosphorylation site in the shelterin subunit TRF2 at ser365. Dephosphorylation of TRF2 in S phase by the PP6R3 phosphatase (SAPS3; 610879) provides a narrow window during which the RTEL1 (608833) helicase can transiently access and unwind t-loops to facilitate telomere replication. Rephosphorylation of TRF2 at ser365 outside of S phase is required to release RTEL1 from telomeres, which not only protects t-loops from promiscuous unwinding and inappropriate activation of ATM, but also counteracts replication conflicts at DNA secondary structures that arise within telomeres and across the genome. Hence, Sarek et al. (2019) concluded that a phospho-switch in TRF2 coordinates the assembly and disassembly of t-loops during the cell cycle, which protects telomeres from replication stress and an unscheduled DNA damage response.
TRF1 and TRF2 are key components of vertebrate telomeres and bind to double-stranded telomeric DNA as homodimers. Dimerization involves the TRF homology (TRFH) domain, which also mediates interactions with other telomeric proteins. Fairall et al. (2001) determined the crystal structures of the dimerization domains from human TRF1 and TRF2 at 2.9- and 2.2-angstrom resolution, respectively. Despite a modest sequence identity, the 2 TRFH domains have the same entirely alpha-helical architecture, resembling a twisted horseshoe. The dimerization interfaces feature unique interactions that prevent heterodimerization. Mutational analysis of TRF1 corroborated the structural data and underscored the importance of the TRFH domain in dimerization, DNA binding, and telomere localization.
Munoz et al. (2005) generated K5-Terf2 mice that expressed variable levels of TRF2 under control of the 5-prime regulatory region of the bovine keratin K5 promoter, which targets TRF2 to basal cells and stem cells of the epidermis. These mice had a severe phenotype of the skin in response to light, consisting of premature skin deterioration, hyperpigmentation, and increased skin cancer, which resembled the human syndrome xeroderma pigmentosum (see 278700). Keratinocytes from these mice were hypersensitive to ultraviolet irradiation and DNA crosslinking agents. The skin cells of these mice had marked telomere shortening, loss of the telomeric G-strand overhang, and increased chromosomal instability. Telomere loss in these mice was mediated by XPF (278760), a structure-specific nuclease involved in ultraviolet-induced damage repair and mutated in individuals with 1 molecular form of xeroderma pigmentosum. The findings suggested that TRF2 provides a crucial link between telomere function and ultraviolet-induced damage repair, whose alteration underlies genomic instability, cancer, and aging. Munoz et al. (2005) showed that a number of human skin tumors had increased expression of TRF2, further highlighting a role of TRF2 in skin cancer.
Using the K5-Terf2 mouse model, Blanco et al. (2007) showed that increased Trf2 expression combined with telomerase deficiency resulted in a dramatic acceleration of epithelial carcinogenesis that coincided with increased telomere dysfunction and chromosomal instability.
Bailey, S. M., Cornforth, M. N., Kurimasa, A., Chen, D. J., Goodwin, E. H. Strand-specific postreplicative processing of mammalian telomeres. Science 293: 2462-2465, 2001. [PubMed: 11577237] [Full Text: https://doi.org/10.1126/science.1062560]
Bilaud, T., Brun, C., Ancelin, K., Koering, C. E., Laroche, T., Gilson, E. Telomeric localization of TRF2, a novel human telobox protein. Nature Genet. 17: 236-239, 1997. [PubMed: 9326951] [Full Text: https://doi.org/10.1038/ng1097-236]
Blanco, R., Munoz, P., Flores, J. M., Klatt, P., Blasco, M. A. Telomerase abrogation dramatically accelerates TRF2-induced epithelial carcinogenesis. Genes Dev. 21: 206-220, 2007. [PubMed: 17234886] [Full Text: https://doi.org/10.1101/gad.406207]
Bradshaw, P. S., Stavropoulos, D. J., Meyn, M. S. Human telomeric protein TRF2 associates with genomic double-strand breaks as an early response to DNA damage. Nature Genet. 37: 193-197, 2005. [PubMed: 15665826] [Full Text: https://doi.org/10.1038/ng1506]
Broccoli, D., Smogorzewska, A., Chong, L., de Lange, T. Human telomeres contain two distinct Myb-related proteins, TRF1 and TRF2. Nature Genet. 17: 231-235, 1997. [PubMed: 9326950] [Full Text: https://doi.org/10.1038/ng1097-231]
Bryan, T. M., Marusic, L., Bacchetti, S., Namba, M., Reddel, R. R. The telomere lengthening mechanism in telomerase negative immortal human cells does not involve the telomerase RNA subunit. Hum. Molec. Genet. 6: 921-926, 1997. [PubMed: 9175740] [Full Text: https://doi.org/10.1093/hmg/6.6.921]
Chen, Y., Yang, Y., van Overbeek, M., Donigian, J. R., Baciu, P., de Lange, T., Lei, M. A shared docking motif in TRF1 and TRF2 used for differential recruitment of telomeric proteins. Science 319: 1092-1096, 2008. [PubMed: 18202258] [Full Text: https://doi.org/10.1126/science.1151804]
Fairall, L., Chapman, L., Moss, H., de Lange, T., Rhodes, D. Structure of the TRFH dimerization domain of the human telomeric proteins TRF1 and TRF2. Molec. Cell 8: 351-361, 2001. [PubMed: 11545737] [Full Text: https://doi.org/10.1016/s1097-2765(01)00321-5]
Grammatikakis, I., Zhang, P., Panda, A. C., Kim, J., Maudsley, S., Abdelmohsen, K., Yang, X., Martindale, J. L., Motino, O., Hutchison, E. R., Mattson, M. P., Gorospe, M. Alternative splicing of neuronal differentiation factor TRF2 regulated by HNRNPH1/H2. Cell Rep. 15: 926-934, 2016. [PubMed: 27117401] [Full Text: https://doi.org/10.1016/j.celrep.2016.03.080]
Griffith, J. D., Comeau, L., Rosenfield, S., Stansel, R. M., Bianchi, A., Moss, H., de Lange, T. Mammalian telomeres end in a large duplex loop. Cell 97: 503-514, 1999. [PubMed: 10338214] [Full Text: https://doi.org/10.1016/s0092-8674(00)80760-6]
Karlseder, J., Smogorzewska, A., de Lange, T. Senescence induced by altered telomere state, not telomere loss. Science 295: 2446-2449, 2002. [PubMed: 11923537] [Full Text: https://doi.org/10.1126/science.1069523]
Lenain, C., Bauwens, S., Amiard, S., Brunori, M., Giraud-Panis, M.-J., Gilson, E. The Apollo 5-prime exonuclease functions together with TRF2 to protect telomeres from DNA repair. Curr. Biol. 16: 1303-1310, 2006. [PubMed: 16730175] [Full Text: https://doi.org/10.1016/j.cub.2006.05.021]
Lillard-Wetherell, K., Machwe, A., Langland, G. T., Combs, K. A., Behbehani, G. K., Schonberg, S. A., German, J., Turchi, J. J., Orren, D. K., Groden, J. Association and regulation of the BLM helicase by the telomere proteins TRF1 and TRF2. Hum. Molec. Genet. 13: 1919-1932, 2004. [PubMed: 15229185] [Full Text: https://doi.org/10.1093/hmg/ddh193]
Miller, K. M., Rog, O., Cooper, J. P. Semi-conservative DNA replication through telomeres requires Taz1. Nature 440: 824-828, 2006. [PubMed: 16598261] [Full Text: https://doi.org/10.1038/nature04638]
Munoz, P., Blanco, R., Flores, J. M., Blasco, M. A. XPF nuclease-dependent telomere loss and increased DNA damage in mice overexpressing TRF2 result in premature aging and cancer. Nature Genet. 37: 1063-1071, 2005. [PubMed: 16142233] [Full Text: https://doi.org/10.1038/ng1633]
Okamoto, K., Bartocci, C., Ouzounov, I., Diedrich, J. K., Yates, J. R, III, Denchi, E. L. A two-step mechanism for TRF2-mediated chromosome-end protection. Nature 494: 502-505, 2013. [PubMed: 23389450] [Full Text: https://doi.org/10.1038/nature11873]
Opresko, P. L., von Kobbe, C., Laine, J.-P., Harrigan, J., Hickson, I. D., Bohr, V. A. Telomere-binding protein TRF2 binds to and stimulates the Werner and Bloom syndrome helicases. J. Biol. Chem. 277: 41110-41119, 2002. [PubMed: 12181313] [Full Text: https://doi.org/10.1074/jbc.M205396200]
Sakaguchi, A. Y., Padalecki, S. S., Mattern, V., Rodriguez, A., Leach, R. J., McGill, J. R., Chavez, M., Giambernardi, T. A. Chromosomal sublocalization of the transcribed human telomere repeat binding factor 2 gene and comparative mapping in the mouse. Somat. Cell Molec. Genet. 24: 157-163, 1998. [PubMed: 10226653] [Full Text: https://doi.org/10.1023/b:scam.0000007118.47691.d7]
Sarek, G., Kotsantis, P., Ruis, P., Van Ly, D., Margalef, P., Borel, V., Zheng, X.-F., Flynn, H. R., Snijders, A. P., Chowdhury, D., Cesare, A. J., Boulton, S. J. CDK phosphorylation of TRF2 controls t-loop dynamics during the cell cycle. Nature 575: 523-527, 2019. [PubMed: 31723267] [Full Text: https://doi.org/10.1038/s41586-019-1744-8]
Sfeir, A., de Lange, T. Removal of shelterin reveals the telomere end-protection problem. Science 336: 593-597, 2012. [PubMed: 22556254] [Full Text: https://doi.org/10.1126/science.1218498]
Sfeir, A., Kabir, S., van Overbeek, M., Celli, G. B., de Lange, T. Loss of Rap1 induces telomere recombination in the absence of NHEJ or a DNA damage signal. Science 327: 1657-1661, 2010. [PubMed: 20339076] [Full Text: https://doi.org/10.1126/science.1185100]
Stavropoulos, D. J., Bradshaw, P. S., Li, X., Pasic, I., Truong, K., Ikura, M., Ungrin, M., Meyn, M. S. The Bloom syndrome helicase BLM interacts with TRF2 in ALT cells and promotes telomeric DNA synthesis. Hum. Molec. Genet. 11: 3135-3144, 2002. [PubMed: 12444098] [Full Text: https://doi.org/10.1093/hmg/11.25.3135]
van Steensel, B., Smogorzewska, A., de Lange, T. TRF2 protects human telomeres from end-to-end fusions. Cell 92: 401-413, 1998. [PubMed: 9476899] [Full Text: https://doi.org/10.1016/s0092-8674(00)80932-0]
Wang, R. C., Smogorzewska, A., de Lange, T. Homologous recombination generates t-loop-sized deletions at human telomeres. Cell 119: 355-368, 2004. [PubMed: 15507207] [Full Text: https://doi.org/10.1016/j.cell.2004.10.011]
Williams, E. S., Stap, J., Essers, J., Ponnaiya, B., Luijsterburg, M. S., Krawczyk, P. M., Ullrich, R. L., Aten, J. A., Bailey, S. M. DNA double-strand breaks are not sufficient to initiate recruitment of TRF2. Nature Genet. 39: 696-699, 2007. [PubMed: 17534357] [Full Text: https://doi.org/10.1038/ng0607-696]
Ye, J., Lenain, C., Bauwens, S., Rizzo, A., Saint-Leger, A., Poulet, A., Benarroch, D., Magdinier, F., Morere, J., Amiard, S., Verhoeyen, E., Britton, S., and 11 others. TRF2 and Apollo cooperate with topoisomerase 2-alpha to protect human telomeres from replicative damage. Cell 142: 230-242, 2010. [PubMed: 20655466] [Full Text: https://doi.org/10.1016/j.cell.2010.05.032]
Zhu, X.-D., Kuster, B., Mann, M., Petrini, J. H. J., de Lange, T. Cell-cycle-regulated association of RAD50/MRE11/NBS1 with TRF2 and human telomeres. Nature Genet. 25: 347-352, 2000. [PubMed: 10888888] [Full Text: https://doi.org/10.1038/77139]