{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Martin A"],"funding":["American Cancer Society","NHLBI NIH HHS","Jane Coffin Childs","California Institute for Regenerative Medicine","National Institutes of Health","NIH","Siebel Stem Cell Institute","NIGMS NIH HHS","CRISPR Cures for Cancer Initiative"],"pagination":["445-462"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC11960693"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["39(7-8)"],"pubmed_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 "],"journal":["Genes & development"],"pubmed_title":["Active telomere elongation by a subclass of cancer-associated POT1 mutations."],"pmcid":["PMC11960693"],"funding_grant_id":["EDUC4-12790","R01-HL131744","R35 GM134922","R35-GM134922","133396-RSG-19-029-01-DMC","R01 HL131744"],"pubmed_authors":["Li H","Gao J","Song YS","Schabort J","Ghanim GE","Bartke-Croughan R","Hockemeyer D","Martin A","Boyle J","Preetham A","Jagota M","Tran S","Jenkins S","Ho R","Lu R"],"additional_accession":[]},"is_claimable":false,"name":"Active telomere elongation by a subclass of cancer-associated POT1 mutations.","description":"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 ","dates":{"release":"2025-01-01T00:00:00Z","publication":"2025 Apr","modification":"2026-06-02T18:04:06.164Z","creation":"2025-07-01T03:05:29.1Z"},"accession":"S-EPMC11960693","cross_references":{"pubmed":["40015989"],"doi":["10.1101/gad.352492.124"]}}