Telomeric repeat-binding factor 2 and Protection of telomeres protein 1 complex (TRF2-POT1 complex)

The Shelterin complex, specifically involving Telomeric Repeat-Binding Factor 2 (TRF2) and Protection of Telomeres Protein 1 (POT1), is a specialized protein assembly dedicated to protecting the ends of eukaryotic chromosomes (Palm & de Lange, 2008, Annu Rev Genet). TRF2 binds to double-stranded telomeric DNA and is crucial for the formation of T-loops, which sequester the chromosome ends from being recognized as double-strand breaks. POT1 binds to the single-stranded 3' overhang, preventing the activation of the ATR-mediated DNA damage response (Denchi & de Lange, 2007, Nature). Together, these proteins prevent inappropriate DNA repair activities, such as non-homologous end joining (NHEJ) and homology-directed repair (HDR), at telomeres. In many cancers, these proteins are overexpressed or mutated to allow for continued cell proliferation and avoidance of senescence (Pinzaru et al., 2016, Nat Genet). Therapeutic strategies targeting TRF2 and POT1 aim to uncap telomeres, selectively inducing apoptosis or senescence in malignant cells that rely on telomere maintenance for immortality. Small molecule inhibitors and G-quadruplex stabilizers are currently being explored to disrupt these complexes and trigger telomere dysfunction as a potent anti-cancer strategy.

Other names

Shelterin complexTelosomeTERF2-POT1 complexTRF2-POT1-TPP1-TIN2 complex

Disruption of the TRF2 and POT1 complexes leads to telomere uncapping, which triggers a DNA damage response (DDR) at chromosome ends. This results in the formation of telomere-dysfunction induced foci (TIFs), leading to cell cycle arrest, senescence, or apoptosis in cancer cells (de Lange, 2005, Genes & Dev).