{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:51:09Z","timestamp":1760143869506,"version":"build-2065373602"},"reference-count":51,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2024,3,2]],"date-time":"2024-03-02T00:00:00Z","timestamp":1709337600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["RO1-DK067339"],"award-info":[{"award-number":["RO1-DK067339"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>In autosomal dominant polycystic kidney disease (ADPKD) with germline mutations in a PKD1 or PKD2 gene, innumerable cysts develop from tubules, and renal function deteriorates. Second-hit somatic mutations and renal tubular epithelial (RTE) cell death are crucial features of cyst initiation and disease progression. Here, we use established RTE lines and primary ADPKD cells with disease-associated PKD1 mutations to investigate genomic instability and DNA damage responses. We found that ADPKD cells suffer severe chromosome breakage, aneuploidy, heightened susceptibility to DNA damage, and delayed checkpoint activation. Immunohistochemical analyses of human kidneys corroborated observations in cultured cells. DNA damage sensors (ATM\/ATR) were activated but did not localize at nuclear sites of damaged DNA and did not properly activate downstream transducers (CHK1\/CHK2). ADPKD cells also had the ability to transform, as they achieved high saturation density and formed colonies in soft agar. Our studies indicate that defective DNA damage repair pathways and the somatic mutagenesis they cause contribute fundamentally to the pathogenesis of ADPKD. Acquired mutations may alternatively confer proliferative advantages to the clonally expanded cell populations or lead to apoptosis. Further understanding of the molecular details of aberrant DNA damage responses in ADPKD is ongoing and holds promise for targeted therapies.<\/jats:p>","DOI":"10.3390\/ijms25052936","type":"journal-article","created":{"date-parts":[[2024,3,4]],"date-time":"2024-03-04T05:31:12Z","timestamp":1709530272000},"page":"2936","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The Link between Autosomal Dominant Polycystic Kidney Disease and Chromosomal Instability: Exploring the Relationship"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0357-9017","authenticated-orcid":false,"given":"Phang-Lang","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Biological Chemistry, University of California, Irvine, CA 92697, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6391-821X","authenticated-orcid":false,"given":"Chi-Fen","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Biological Chemistry, University of California, Irvine, CA 92697, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hugo Y.-H.","family":"Lin","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan"},{"name":"Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan"},{"name":"Department of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel J.","family":"Riley","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Nephrology, University of Texas Health, San Antonio, TX 78245, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yumay","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Endocrinology, University of California, Irvine, CA 92697, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,3,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1146\/annurev.med.60.101707.125712","article-title":"Polycystic Kidney Disease","volume":"60","author":"Harris","year":"2009","journal-title":"Ann. 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