Human telomerase is directly regulated by non-telomeric TRF2-G-quadruplex interaction

Abstract

Human telomerase is directly regulated by nontelomeric TRF2-G-quadruplex interactionGraphical abstract Highlights d Non-telomeric TRF2 suppresses re-activated human telomerase in glioblastoma cells d PRC2 recruitment depends on the TRF2 hTERT-Gquadruplex interaction d Clinically deleterious hTERT promoter mutations disrupt G4-TRF2 association d G4 stabilization reinstates TRF2-induced hTERT repression in patient glioblastoma

Telomere length sensitive regulation of Interleukin Receptor 1 type 1 (IL1R1) by the shelterin protein TRF2 modulates immune signalling in the tumour microenvironment

“…Although TRF2 was implicated in influencing Natural Killer (NK) cells and infiltration of Myeloid Derived immuno-Suppressive Cells (MDSC) 50,51 underlying mechanisms were unclear. We recently noted transcription repression of telomerase (hTERT) to be TRF2mediated in a PRC2-repressor dependent fashion 52 .This, interestingly, suggests the emerging role of TRF2 as a transcriptional modulator with repressor/activator (as shown here) functions depending on cofactor engagement that is possibly contextual. The RNA template of telomerase (TERC), but not hTERT, was higher in TNBC-LT (Supplementary Figure 5A), and telomerase activity (from 64 TNBC samples) did not positively correlate with telomere length (Supplementary Figure 5B) possibly due to the complexity of telomerase/TME interdependence as also noted earlier 19,53,54 .…”

Telomeres expand sphere of influence: emerging molecular impact of telomeres in non-telomeric functions

“…Non-telomeric functions of TRF1 and TRF2 Besides RAP1, TRF1 and TRF2 were reported to bind to ~180 interstitial sites [13][14][15]. Recently, TRF2 binding was reported at thousands of non-telomeric sites [20], and TRF2-meditated regulation of several genes was observed (described in the following section) [21][22][23][24][25] (Figure 2C). Non-telomeric TRF2 was also shown to regulate vascularization through VEGF-A [26] and PDGFR-β [21], to reduce the recruitment and activation of natural killer (NK) cells [27], and to induce the recruitment of myeloid-derived suppressor cells (MDSCs) that promote tumor growth through immunosuppression [28].…”

Telomerase in Cancer: Function, Regulation, and Clinical Translation

“…The diversity of signaling inputs and TFs that oversee TERT transcription enable combinatorial control of telomerase function in response to intracellular and extracellular conditions. (B) The human TERT promoter harbors binding sites for the major transcriptional regulators of TERT expression [shown as approximate nucleotide position relative to the transcription start site (TSS)] [64][65][66][67][68]. TFs shown above and below the chromosome (rectangle) have binding motifs located on overlapping segment of the TERT promoter, rather than binding in opposing orientations.…”

“…Another tumor suppressor, CCCTC-binding factor (CTCF), blocks TERT expression by binding within its open reading frame and physically displacing the transcription machinery [92,93]. Intriguingly, the telomere-binding protein TRF2 exerts direct transcriptional control over TERT expression by binding specific DNA secondary structural elements and recruiting the polycomb repressive (PRC) complex to the TERT promoter [64], suggesting that telomere-binding proteins act as critical regulators of telomerase activity through both telomere-dependent and -independent mechanisms. Taken together, these findings illuminate the myriad pathways that integrate intracellular and extracellular signals to enable combinatorial control of telomerase function.…”