POT1 (protection of telomeres 1) is a critical single-stranded telomeric DNA-binding protein that serves as a core component of the shelterin complex, a six-protein assembly that protects chromosome 7 from inappropriate DNA damage responses 1. POT1 directly recognizes telomeric TTAGGG repeats with high specificity, binding to single-stranded 5'-TAGGGTTAG-3' sequences 1. The protein functions through multiple mechanisms: it recruits and regulates the CST-Polα/primase complex to telomeres through phosphorylation-dependent interactions, maintaining an inactive state until telomerase extension is complete, then releasing CST-Polα/primase for C-strand fill-in synthesis 2. POT1 also assembles as a heterodimer with TPP1 to recruit telomerase to telomeres, stabilizing telomeric DNA and enhancing telomerase processivity 3. Without shelterin's protective activity, telomeres become exposed to DNA damage surveillance machinery and undergo inappropriate repair processing 1. Clinically, germline POT1 mutations cause diverse phenotypes: loss-of-function mutations produce long telomere syndrome with predisposition to clonal hematopoiesis and multiple cancers including lymphomas and solid tumors 4, while oncogenic mutations are implicated in familial melanoma and glioma predisposition 56. POT1 mutations have also been identified as rare transforming alleles in cancer genomics studies 7.