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10.1172/JCI80657 http://scihub22266oqcxt.onion/10.1172/JCI80657 C4588305!4588305!26301811     free     free     free Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534       J+Clin+Invest 2015 ; 125 (9): 3657-66 Nephropedia Template TP {{tp|p=26301811|t=2015. DNA replication stress underlies renal phenotypes in CEP290-associated Joubert syndrome |pdf=|usr=}}{{26301811}} gab.com Text DNA replication stress underlies renal phenotypes in CEP290-associated Joubert syndrome JO: J Clin Invest http://www.kidney.de/pget.php?&tw=1&pmid=26301811 #FOAvip 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 link between CEP290 and DNA replication stress and suggest CDK inhibition as a potential treatment strategy for a wide range of ciliopathy syndromes. Twit Text FOAVip DNA replication stress underlies renal phenotypes in CEP290-associated Joubert syndrome ????J Clin Invest http://www.kidney.de/pget.php?&tw=1&pmid=26301811 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=26301811 #FOAvip English Wikipedia <ref>{{Cite pmid|26301811}}</ref> DNA replication stress underlies renal phenotypes in CEP290-associated Joubert syndrome #MMPMID26301811 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 J Clin Invest 2015[Sep]; 125 (9): 3657-66 PMID26301811show ga 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 link between CEP290 and DNA replication stress and suggest CDK inhibition as a potential treatment strategy for a wide range of ciliopathy syndromes. äDNA replication stress underlies renal phenotypes in CEP290-associated(epmc).pdf DeepDyve Pubget Overpricing