TERF1 (Telomeric Repeat Binding Factor 1)

More genetic analyses indicated that BAF1 and LEM2 contribute to safeguarding of telomeres during nuclear envelope reassembly. Because defects in nuclear envelope dynamics and chromatin-membrane coupling are hallmarks of disorders associated with nuclear deformation and fragility, including aging and cancer, our findings contribute a new angle into these conditions and suggest potential targets for selectively modulating telomere maintenance pathways.

We discovered a first-in-class inhibitor of the TRF1:TIN2 interaction (compound 40) that binds to TRF1TRFH with a KD of 29 µM (95% CI: 20-41 µM), displaces a TIN2 probe with an IC50 of 67 µM (95% CI: 10-120 µM), and expels TRF1 from purified shelterin. Aided by a novel crystal system of TRF1TRFH, we characterised fragments binding in a hotspot at the TRF1:TIN2 interface; these will serve as a starting point for the structure-guided development of potent inhibitors of TRF1 protein:protein interactions to disrupt shelterin complex assembly.

Moreover, our analysis identified six subtype-specific drugs, such as KU_55933 and Cyclophosphamide, that were more sensitive to PS1. In conclusion, this study successfully constructed and evaluated a pathway-based molecular subtype and classification model for HCC, thoroughly investigated the biological and multi-omics differences between subtypes. Additionally, the identification of three telomere-associated biomarkers offers guidance and a theoretical basis for personalized treatment and clinical use of drugs for HCC patients.

Unlike the recently reported results from the United States, TRG variants do not seem to play a role in sporadic or familial TC samples from the Saudi Arabian population. These results suggest that the role of TRG variants may vary among different ethnic populations and call for validation of these findings in diverse populations.

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.

Mechanistically, PINX1 facilitated ILF3 degradation via SPOP, suppressed the PI3K-AKT-mTOR pathway, inhibited tumor proliferation, and enhanced cisplatin sensitivity in NPC cells. These findings highlight the tumor-suppressive role of PINX1 and underscore its potential as a therapeutic target in NPC.

Upon nutrient starvation, PinX1 is acetylated at K43, K133, K140, K149, K190, K222, which hinders its binding to POLR1G leading to disassembly of PIC. Collectively, our findings uncover a novel role of PinX1 and its acetylation, fine-tuning nucleolar transcription to stress signaling.

Simvastatin effectively inhibited the proliferation and migration of colon cancer cells and promoted apoptosis through the modulation of key targets, such as SERPINE1 and the cGMP/PKG signaling pathway.

In animal study, this active nanocomplex revealed powerful and selective therapeutic tumor-targeting effects, with no evidence of toxicity to healthy tissues. DE-Cu4O3 nanocomplex is deemed as promising nanomedicine for NSCLC.

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.

Knockdown of TIN2 could restrained telomerase function and the malignant abilities of proliferation, metastasis and autophagy but induced ferroptosis of GC cells, which suggested that targeting TIN2 might be a therapeutic strategy for GC.

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.