Shelterin

Shelterin is a conserved protein complex that binds telomeres and protects chromosome ends while regulating telomere length. In humans, it comprises six subunits: TRF1, TRF2, POT1, TIN2, TPP1 (also known as ACD), and RAP1. The complex associates with telomeric DNA through two modules: TRF1 and TRF2 bind double-stranded telomeric repeats, while POT1 binds the single-stranded G-rich overhang. TIN2 acts as a central scaffold linking the telomere-binding proteins to POT1-TPP1, and RAP1 is recruited to telomeres via TRF2.

Functionally, shelterin protects chromosome ends from being recognized as DNA damage and regulates telomere maintenance. It suppresses the activation of the ATM and ATR DNA damage response pathways at telomeres, helping to prevent end-to-end chromosome fusions and inappropriate repair. It also modulates telomere length by regulating access of telomerase and nucleases to telomeres and by stabilizing the t-loop structure that conceals the ends from repair machinery.

Biological significance of shelterin lies in maintaining genome stability and normal cellular proliferation. Disruption of shelterin components leads to telomere uncapping, activation of DNA damage signals, telomere fusions, and genome instability. The complex is essential in vertebrates, and variations of its subunit composition exist across species.

Clinical and research relevance includes links between mutations or misregulation of shelterin components and telomere biology disorders, cancer, and aging contexts, reflecting the central role of shelterin in telomere biology.