Active telomere elongation by a subclass of cancer-associated POT1 mutations.
Publication Year:
2025
PubMed ID:
40015989
Public Summary:
Chromosome ends are protected by special structures called telomeres, which are essential for maintaining chromosome stability and limit cell growth. A protein called POT1 that is present at telomeres plays an unusual function in regulating the length of these protective ends. Here we systematically test many mutations to POT1 to understand how these changes affect telomere maintenance. First, we show that POT1 is essential for ensuring stability of telomeres. We also show that some mutations weaken POT1’s ability to protect telomeres, while others unexpectedly cause telomeres to become too long. This excessive telomere elongation may allow cancer cells to keep dividing when they should not. These findings further our understanding how POT1 mutations can drive cancer development.
Scientific Abstract:
Mutations in the shelterin protein POT1 are associated with diverse cancers and thought to drive carcinogenesis by impairing POT1's suppression of aberrant telomere elongation. To classify clinical variants of uncertain significance (VUSs) and identify cancer-driving loss-of-function mutations, we developed a locally haploid human stem cell system to evaluate >1900 POT1 mutations, including >600 VUSs. Unexpectedly, many validated familial cancer-associated POT1 (caPOT1) mutations are haplosufficient for cellular viability, indicating that some pathogenic alleles do not act through a loss-of-function mechanism. Instead, POT1's DNA damage response suppression and telomere length control are genetically separable. ATR inhibition enables isolation of frameshift mutants, demonstrating that the only essential function of POT1 is to repress ATR. Furthermore, comparison of caPOT1 and frameshift alleles reveals a class of caPOT1 mutations that elongate telomeres more rapidly than full loss-of-function alleles. This telomere length-promoting activity is independent from POT1's role in overhang sequestration and fill-in synthesis.
