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Lookup NU author(s): Dr Ann Marie Hynes, Dr Shalabh Srivastava, Dr Colin Miles, Professor John SayerORCiD
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Juvenile ciliopathy syndromes that are associated with renal cysts and premature renal failure are commonly the result of mutations in the gene encoding centrosomal protein CEP290. In addition to centrosomes and the transition zone at the base of the primary cilium, CEP290 also localizes to the nucleus; however, the nuclear function of CEP290 is unknown. Here, we demonstrate that reduction of cellular CEP290 in primary human and mouse kidney cells as well as in zebrafish embryos leads to enhanced DNA damage signaling and accumulation of DNA breaks ex vivo and in vivo. Compared with those from WT mice, primary kidney cells from Cep290-deficient mice exhibited supernumerary centrioles, decreased replication fork velocity, fork asymmetry, and increased levels of cyclin-dependent kinases (CDKs). Treatment of Cep290-deficient cells with CDK inhibitors rescued DNA damage and centriole number. Moreover, the loss of primary cilia that results from CEP290 dysfunction was rescued in 3D cell culture spheroids of primary murine kidney cells after exposure to CDK inhibitors. Together, our results provide a linIc between CEP290 and DNA replication stress and suggest MK inhibition as a potential treatment strategy for a wide range of ciliopathy syndromes.
Author(s): Slaats GG, Saldivar JC, Bacal J, Zeman MK, Kile AC, Hynes AM, Srivastava S, Nazmutdinova J, den Ouden K, Zagers MS, Foletto V, Verhaar MC, Miles C, Sayer JA, Cimprich KA, Giles RH
Publication type: Article
Publication status: Published
Journal: Journal of Clinical Investigation
Year: 2015
Volume: 125
Issue: 9
Pages: 3657-3666
Print publication date: 01/09/2015
Online publication date: 24/08/2015
Acceptance date: 10/07/2015
ISSN (print): 0021-9738
ISSN (electronic): 1558-8238
Publisher: American Society for Clinical Investigation
URL: http://dx.doi.org/10.1172/JCI80657
DOI: 10.1172/JCI80657
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