Disease relevance of TERF2

• Here we investigated the expressions of the mRNAs encoded by the TERF1 and TERF2 genes using in situ hybridization in surgically resected specimens [28 AAHs (11 lesions were interpreted as low-grade AAH, and 17 were interpreted as high-grade AAH) and 40 peripherally located bronchioloalveolar carcinoma (BAC) [1].
• TERF2 SNPs and haplotypes were not significantly associated with aplastic anemia [2].
• A second paper goes on to demonstrate that overexpression of TERF2 produces mouse phenotypes similar to those associated with xeroderma pigmentosum, such as cellular hypersensitivity to UV radiation and DNA crosslinking agents, and telomere shortening and chromosome instability in response to DNA damage [3].
• Expression of mRNAs for telomeric repeat binding factor (TRF)-1 and TRF2 in atypical adenomatous hyperplasia and adenocarcinoma of the lung [1].
• We suggest that the upregulation of specific telomere-binding proteins like TRF2 may contribute to telomere maintenance in malignant lymphoma [4].

High impact information on TERF2

• Furthermore, overexpression of TRF2 inhibits DSB-induced phosphorylation of ATM signaling targets [5].
• 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 [5].
• Human telomeric protein TRF2 associates with genomic double-strand breaks as an early response to DNA damage [5].
• We now show that TRF2 associates with photo-induced DSBs in nontelomeric DNA in human fibroblasts within 2 s of irradiation [5].
• These findings suggest that TRF2 provides a crucial link between telomere function and ultraviolet-induced damage repair, whose alteration underlies genomic instability, cancer and aging [6].

Chemical compound and disease context of TERF2

• Results showed that treatment of human gastric cancer MGC-803 cells with arsenic trioxide could cause up-regulation of telomeric repeat binding factor TRF1 and TRF2 mRNA and protein levels, and induced G2/M phase arrest and cell apoptosis [7].
• TRF2 was up-regulated in P19 embryonal carcinoma cells at the early stage of induced neural differentiation with retinoic acid treatment [8].
• Results also indicate that cellular levels of TRF2 may play a critical role in MNNG-induced cell cycle arrest and apoptosis of colon cancer cells [9].

Biological context of TERF2

• Characterization of the telomere complex, TERF1 and TERF2 genes in muntjac species with fusion karyotypes [10].
• We hypothesized that genetic variation in two genes critical in telomere biology, TERF1 and TERF2, could be a risk factor for AA [2].
• Assignment of TERF1 to chicken chromosome 2q32 and TERF2 to chicken microchromosome 11 by fluorescence in situ hybridization [11].
• We localized the transcribed TERF2 gene to human chromosome 16q22.1, tightly linked to the EST HUM000S343 [12].
• Telomere repeat binding factor 2 (TERF2) is one of two recently cloned mammalian telomere binding protein genes [12].

Anatomical context of TERF2

• Human TATA-binding protein-related factor-2 (hTRF2) stably associates with hTFIIA in HeLa cells [13].
• In vivo TRF2-GFP and immuno-staining studies in muntjac cell lines revealed telomeric TRF2 localization, while deletion of the DNA binding domain abrogated this localization, suggesting muntjac TRF2 represents a functional telomere protein [10].
• RESULTS: TRF1, TRF2 and TIN2 mRNAs were significantly down-regulated in cancers compared to non-cancerous mucosa [14].
• Next, the down-regulation of hTERT transcription by Tax in HTLV-1 transformed or in Tax-expressing T lymphocytes is found to correlate with a significant increase of TRF2 and/or Pot1 mRNAs [15].
• TRF1 and TRF2 were also studied using an immunohistochemical method to determine the frequency of these factors in cell nuclei [16].

Associations of TERF2 with chemical compounds

• Flow cytometry measurements indicated that the increase of TRF1 and TRF2 proteins is related to oxidative stress by arsenic trioxide [7].
• We refer to this protein as Apollo and report that Apollo has the ability to localize to telomeres through an interaction with the shelterin component TRF2 [17].
• This could be correlated to the actinomycin D-suppressed relocalization of TRF2 from the nucleolus to the telomeres during mitosis [18].
• However, small but significant differences are observed; in contrast to the minor groove recognition of TRF1, in which an arginine residue recognizes the TT sequence, a lysine residue of TRF2 interacts with the TT part [19].
• TRF2 is a telomere binding protein that is involved in protecting the G-strand overhang, a 3', guanine-rich, overhang at the telomere terminus [20].

Physical interactions of TERF2

• The MRN complex is also involved in telomere maintenance, as demonstrated by the shortened telomeres in NBS primary human fibroblasts and the association of NBS1 with the telomere-binding protein TRF2 [21].
• We show here that TIN2 also interacts with TRF2 in vitro and in yeast and mammalian cells [22].
• Here, we show that fusions of hTERT containing different mutations in this domain to the telomere binding protein hTRF2 redirected the mutated hTERT to telomeres and rescued its in vivo functions [23].
• The treatment of human EcR293 cells by telomestatin induces a dramatic and rapid delocalization of POT1 from its normal telomere sites but does not affect the telomere localization of the double-stranded telomere-binding protein TRF2 [24].
• It involves a stretch of at least 25 amino acids at the C-terminus of hRap1 that interact with TRF2 [25].

Co-localisations of TERF2

• In human cells, we report that WRN co-localizes and physically interacts with the critical telomere maintenance protein TRF2 [26].
• BLM co-localizes with TRF2 in foci actively synthesizing DNA during late S and G2/M; co-localization increases in late S and G2/M when ALT is thought to occur [27].

Regulatory relationships of TERF2

• Telomere-binding protein TRF2 binds to and stimulates the Werner and Bloom syndrome helicases [26].
• Furthermore, WRN RNAi-induced DNA damage was suppressed by overexpression of the telomere-binding protein TRF2 [28].
• In particular, we show that telomerase deficiency dramatically accelerates TRF2-induced epithelial carcinogenesis in K5TRF2/Terc-/- mice, coinciding with increased chromosomal instability and DNA damage [29].
• TRF2 inhibition promotes anchorage-independent growth of telomerase-positive human fibroblasts [30].
• Here we report that TRF2-induced telomere shortening is abrogated in human cells deficient in XPF, demonstrating that XPF-ERCC1 is required for TRF2-promoted telomere shortening [31].

Other interactions of TERF2

• However, while scRap1 binds telomeric DNA directly, hRap1 is recruited to telomeres by TRF2 [32].
• Our results implicate TRF2 in an initial stage of DSB recognition and processing that occurs before association of ATM with DSBs and activation of the ATM-dependent DSB response network [5].
• Here we show by nanoelectrospray tandem mass spectrometry that RAD50 protein is present in TRF2 immunocomplexes [33].
• Thus, in less than 50 PDs, the length of telomeres increased 3-8-fold beyond physiological size, while telomere-bound TRF1 and TRF2 increased proportionally to telomere length [34].
• Up-regulation of telomere-binding proteins, TRF1, TRF2, and TIN2 is related to telomere shortening during human multistep hepatocarcinogenesis [35].
• Our genome-wide target analysis revealed phosphatase nuclear targeting subunit (PNUTS) and microcephalin 1 (MCPH1) as previously unreported telomere-associated proteins that directly interact with TRF2 via the [Y/F]XL motif [36].

Analytical, diagnostic and therapeutic context of TERF2

• The expressions of TERF1 and TERF2 mRNA detected by in situ hybridization were scored positive in 36% and 82% of low-grade AAH, 65% and 83% of high-grade AAH, and 88% and 88% of BAC, respectively [1].
• Electron microscopy reported here demonstrated that TRF2 can remodel linear telomeric DNA into large duplex loops (t loops) in vitro [37].
• Furthermore, the loss of TRF2 did not compromise liver regeneration after partial hepatectomy [38].
• BLM interacts in vivo with the telomeric protein TRF2 in ALT cells, as detected by FRET and co-immunoprecipitation [39].
• Unexpectedly immunofluorescence studies revealed a prominent nucleolar localization of TRF2 in human cells, which appeared as discrete dots with sizes similar to those present in the nucleoplasm [18].

References