Beyond End Protection: Shelterin, POT1 Dysfunction, and Telomere Replication Stress in Cancer

Telomeres (chromosome-end nucleoprotein complexes) are prone to replication fork stalling because of their G-rich repetitive sequences, G-quadruplexes, t-loops, oxidative lesions, and telomeric R-loops generated when telomeric repeat-containing RNA (TERRA) hybridizes with telomeric DNA. In this review, we will summarize how telomeres are replicated and maintained and the mechanisms by which replication stress occurs at telomeres. Subsequently, we will review the role of POT1 mutations in cancer development and pathology and discuss therapeutic strategies targeting telomere biology in cancer.