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High-resolution crystallographic structures reveal that the junction is capped by POT1 through a \u201cPOT-hole\u201d surface, the mutation of which compromises junction protection in vitro and telomeric 5\u2032-end definition and DDR suppression in human cells. Whereas both mouse POT1 paralogs bind the single-stranded overhang, POT1a, not POT1b, contains a POT-hole and binds the junction, which explains POT1a\u2019s sufficiency for end protection. Our study shifts the paradigm for DDR suppression at telomeres by highlighting the importance of protecting the double-stranded\u2013single-stranded junction.<\/jats:p>","DOI":"10.1126\/science.adi2436","type":"journal-article","created":{"date-parts":[[2023,8,17]],"date-time":"2023-08-17T14:00:45Z","timestamp":1692280845000},"page":"771-778","update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":49,"title":["Human POT1 protects the telomeric ds-ss DNA junction by capping the 5\u2032 end of the chromosome"],"prefix":"10.1126","volume":"381","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7445-8407","authenticated-orcid":true,"given":"Valerie M.","family":"Tesmer","sequence":"first","affiliation":[{"name":"Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, 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