{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T22:12:52Z","timestamp":1769119972128,"version":"3.49.0"},"reference-count":46,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2021,9,29]],"date-time":"2021-09-29T00:00:00Z","timestamp":1632873600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["1164128; 1138533"],"award-info":[{"award-number":["1164128; 1138533"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"name":"PKD Australia","award":["2018"],"award-info":[{"award-number":["2018"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>DNA-dependent protein kinase (DNA-PK) is a serine\/threonine protein involved in DNA damage response (DDR) signaling that may mediate kidney cyst growth in autosomal dominant polycystic kidney disease (ADPKD) due to its pleiotropic effects on proliferation and survival. To test this hypothesis, the expression of DNA-PK in human ADPKD and the in vitro effects of DNA-PK inhibition in a three-dimensional model of Madin-Darby Canine Kidney (MDCK) cyst growth and human ADPKD cells were assessed. In human ADPKD, the mRNA expression for all three subunits of the DNA-PK complex was increased, and using immunohistochemistry, the catalytic subunit (DNA-PKcs) was detected in the cyst lining epithelia of human ADPKD, in a focal manner. In vitro, NU7441 (a DNA-PK kinase inhibitor) reduced MDCK cyst growth by up to 52% after long-term treatment over 6\u201312 days. Although human ADPKD cell lines (WT9-7\/WT9-12) did not exhibit synthetic lethality in response to DNA-PK kinase inhibition compared to normal human kidney cells (HK-2), the combination of low-dose NU7441 enhanced the anti-proliferative effects of sirolimus in WT9-7 and WT9-12 cells by 17 \u00b1 10% and 11 \u00b1 7%, respectively. In conclusion, these preliminary data suggest that DNA-PK mediates kidney cyst growth in vivo without a synthetically lethal interaction, conferring cell-specificity in human ADPKD cells. NU7441 enhanced the anti-proliferative effects of rapamycin complex 1 inhibitors, but the effect was modest.<\/jats:p>","DOI":"10.3390\/ijms221910512","type":"journal-article","created":{"date-parts":[[2021,9,29]],"date-time":"2021-09-29T08:27:44Z","timestamp":1632904064000},"page":"10512","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Role of DNA-Dependent Protein Kinase in Mediating Cyst Growth in Autosomal Dominant Polycystic Kidney Disease"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3770-9227","authenticated-orcid":false,"given":"Ashley N.","family":"Chandra","sequence":"first","affiliation":[{"name":"Michael Stern Laboratory for Polycystic Kidney Disease, Westmead Institute for Medical Research, The University of Sydney, Westmead, NSW 2145, Australia"},{"name":"Department of Renal Medicine, Westmead Hospital, Western Sydney Local Health District, Westmead, NSW 2145, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sayanthooran","family":"Saravanabavan","sequence":"additional","affiliation":[{"name":"Michael Stern Laboratory for Polycystic Kidney Disease, Westmead Institute for Medical Research, The University of Sydney, Westmead, NSW 2145, Australia"},{"name":"Department of Renal Medicine, Westmead Hospital, Western Sydney Local Health District, Westmead, NSW 2145, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2147-0998","authenticated-orcid":false,"given":"Gopala K.","family":"Rangan","sequence":"additional","affiliation":[{"name":"Michael Stern Laboratory for Polycystic Kidney Disease, Westmead Institute for Medical Research, The University of Sydney, Westmead, NSW 2145, Australia"},{"name":"Department of Renal Medicine, Westmead Hospital, Western Sydney Local Health District, Westmead, NSW 2145, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1038\/317542a0","article-title":"A highly polymorphic DNA marker linked to adult polycystic kidney disease on chromosome 16","volume":"317","author":"Reeders","year":"1985","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.1681\/ASN.V641125","article-title":"Polycystic kidney disease. 1: Identification and analysis of the primary defect","volume":"6","author":"Harris","year":"1995","journal-title":"J. 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