TERF2 (Telomeric Repeat Binding Factor 2)

TERF2 knockdown induced apoptosis, suppressed cell proliferation, and downregulated the E2F pathway, while simultaneously enhancing cuproptosis susceptibility, as evidenced by reduced half-maximal inhibitory concentration (IC50) values of the elesclomol-copper (ES-Cu)...Downregulation of TERF2 inhibits the AML cell proliferation, induces apoptosis, and modulates cuproptosis sensitivity possibly via the E2F-mediated pathway. Targeting TERF2 not only inhibits proliferation but also unlocks cuproptosis as a therapeutic vulnerability, offering a potential strategy for AML.

Mechanistically, we found that telomere shortening in mast cells from children with non-PTD KIT mutations is linked with increased p38 MAP-kinase activation, resulting in lower TRF2 occupancy on telomeres. Thus, non-PTD KIT mutations trigger distinct signaling pathways leading to telomere shortening and cellular senescence, providing mechanistic insights into the differing outcomes between childhood- and adult-onset mastocytosis.

Our work shows, for the first time, a broad overview on the extra-telomeric role of TRF2 in human cancer, further revealing a new axis through which TRF2 contributes to cancer progression.

Conversely, on telomere shortening in iPSCs, TERT promoter-bound TRF2 was restored with a marked reduction in TERT, further supporting the causal role of TL in TERT transcription. Mechanisms of tight control of TERT by TL shown here are likely to have major implications in telomere-related physiologies, particularly, cancer, ageing, and pluripotency.

TRF1-TIN2-TPP1-POT1 tightly associates with telomeres, whereas TRF2-RAP1 binds more dynamically, facilitating the recruitment of co-factors that protect chromosome ends. Altogether, our work provides mechanistic insight into shelterin function in telomere maintenance and advances our understanding of telomeric chromatin architecture.

This review systematically examines: (1) molecular mechanisms linking telomere shortening to oxidative stress (NOX2/PRDX1 axis), epigenetic dysregulation (subtelomeric methylation, H3K9me3 loss), and mitochondrial dysfunction; (2) clinical evidence positioning leukocyte telomere length and telomere-associated proteins (eg, TRF2, POT1) as predictive biomarkers for coronary artery disease, heart failure, and hypertension; and (3) emerging therapeutic strategies ranging from telomerase activation (TA-65, GRN510) to senolytic cocktails (dasatinib + quercetin) and CRISPR (regularly interspersed short palindromic reportsclustered regularly interspaced short palindromic repeats)-based editing (6-29% efficiency in Chinese hamster ovary models). Translationally, we discuss tissue-specific delivery systems to mitigate oncogenic risks of telomerase therapies while emphasizing mitochondrial-targeted approaches for telomere stabilization. This synthesis bridges basic telomere science with clinical cardiology, offering a roadmap for personalized vascular rejuvenation strategies.

This indicates that hTERT variants induce TRF2-mediated telomere compaction that is independent of telomere length, and it plays a dominant role in regulating the DNA damage signaling that induces senescence and blocks replication of human fibroblasts. These observations support the idea that very short telomeres often seen in cancer cells may fail to induce senescence due to selective stabilization of components of the shelterin complex, increasing telomere density, rather than maintaining telomere length via the reverse transcriptase activity of hTERT.

Moreover, high TRF2 could predict the mortality of the breast cancer population to be 3.66 times higher than the lower group. In contrast, telomere length was not associated with overall survival rate nor predicting mortality in five years.

Under 5 Gy radiotherapy, cells treated with this system show a 1.5-fold radiosensitivity increase from AuNCs and a 2.3-fold reduction in clonogenic survival due to telomere deprotection. The AuNC-siRNATRF2 system combines enhanced optical properties with biological functionality, offering a promising approach to augment radiotherapy efficacy by disrupting telomeric protective mechanisms in cancer cells.

In line with this, a spontaneous model of TNBC metastasis, combined with intravital imaging, allowed us to demonstrate that TRF2 promotes cell migration at the primary tumor site and is required for the early steps of the metastatic cascade. In human breast cancers, aberrantly elevated TRF2 expression positively correlates with cancer progression, metastasis, and poor prognosis, identifying TRF2 as a potential target for novel therapeutic strategies against TNBC.

These insights can help overcome challenges posed by ALT + cancers, including their ability to transition from telomerase-dependent states. Targeting ALT-specific vulnerabilities offers a promising direction for developing innovative therapies that exploit the unique biology of ALT-driven tumors.

Furthermore, F2 demonstrated strong antitumor efficacy with minimal toxicity in an MG63-derived xenograft mouse model. These findings demonstrate that F2 is a promising drug candidate for the treatment of osteosarcoma.