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The mechanisms are unresolved, but the human <jats:italic>PKD1<\/jats:italic> tumor suppressor is a good experimental model for identifying the molecular determinants. Inactivation of <jats:italic>PKD1<\/jats:italic> results in autosomal dominant polycystic kidney disease, a very common disorder characterized by the accumulation of fluid-filled cysts and end-stage renal disease. Since human <jats:italic>PKD1<\/jats:italic> follows second hit and mouse <jats:italic>Pkd1<\/jats:italic> heterozygotes do not, we reasoned that there is likely a molecular difference that explains the elevated mutagenesis of the human gene. Here we demonstrate that guanine quadruplex DNA structures are abundant throughout human, but not mouse, <jats:italic>PKD1<\/jats:italic> where they activate the DNA damage response. Our results suggest that guanine quadruplex DNAs provoke DNA breaks in <jats:italic>PKD1<\/jats:italic>, providing a potential mechanism for cystogenesis in autosomal dominant polycystic kidney disease specifically and for the inactivation of guanine quadruplex-rich tumor suppressors generally.<\/jats:p>","DOI":"10.1038\/s41467-024-55684-y","type":"journal-article","created":{"date-parts":[[2025,1,3]],"date-time":"2025-01-03T01:20:28Z","timestamp":1735867228000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["G-quadruplex stabilization provokes DNA breaks in human PKD1, revealing a second hit mechanism for ADPKD"],"prefix":"10.1038","volume":"16","author":[{"given":"Agata M.","family":"Parsons","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-1531-7823","authenticated-orcid":false,"given":"Seth","family":"Byrne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-7514-0580","authenticated-orcid":false,"given":"Jesse","family":"Kooistra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6259-9491","authenticated-orcid":false,"given":"John","family":"Dewey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron L.","family":"Zebolsky","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4356-9841","authenticated-orcid":false,"given":"Gloria","family":"Alvarado","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerrit J.","family":"Bouma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory B.","family":"Vanden Heuvel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7457-5742","authenticated-orcid":false,"given":"Erik D.","family":"Larson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,1,2]]},"reference":[{"key":"55684_CR1","doi-asserted-by":"publisher","first-page":"820","DOI":"10.1073\/pnas.68.4.820","volume":"68","author":"AG Knudson","year":"1971","unstructured":"Knudson, A. 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The authors declare no other competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"121"}}