NEK8 links the ATR-regulated replication stress response and S phase CDK activity to renal ciliopathies.
NEK8 links the ATR-regulated replication stress response and S phase CDK activity to renal ciliopathies.
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DOI：
10.1016/j.molcel.2013.08.006
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发表时间：
2013-08-22
期刊：
影响因子：
16
通讯作者：
Cimprich, Karlene A.
中科院分区：
文献类型：
--
作者：
Choi, Hyo Jei Claudia;Lin, Jia-Ren;Vannier, Jean-Baptiste;Slaats, Gisela G.;Kile, Andrew C.;Paulsen, Renee D.;Manning, Danielle K.;Beier, David R.;Giles, Rachel H.;Boulton, Simon J.;Cimprich, Karlene A.
肾纤毛病变是肾衰竭的主要原因，但其确切病因知之甚少。NEK 8/NPHP 9是与人类和小鼠中的两种肾纤毛病（肾单位结核（NPHP）和多囊肾病）相关的纤毛激酶。在这里，我们确定NEK 8作为ATR介导的复制应激反应的关键效应子。缺乏NEK 8的细胞形成自发的DNA双链断裂（DSB），当复制叉停止时，DSB进一步积累，并且它们表现出减少的叉率、非预定的起点发射和增加的复制叉崩溃。NEK 8通过限制细胞周期蛋白A相关的CDK活性来抑制DSB的形成。引人注目的是，与肾纤毛病变相关的NEK 8突变影响其基因组维持功能。此外，NEK 8突变小鼠的肾脏积累DNA损伤，并且NEK 8的丢失或复制应激类似地破坏3D培养系统中的肾细胞结构。因此，NEK 8是DNA损伤反应的关键组分，其将复制应激与囊性肾病联系起来。
Renal ciliopathies are a leading cause of kidney failure, but their exact etiology is poorly understood. NEK8/NPHP9 is a ciliary kinase associated with two renal ciliopathies in humans and mice, nephronophthisis (NPHP) and polycystic kidney disease. Here, we identify NEK8 as a key effector of the ATR-mediated replication stress response. Cells lacking NEK8 form spontaneous DNA double-strand breaks (DSBs) which further accumulate when replication forks stall, and they exhibit reduced fork rates, unscheduled origin firing, and increased replication fork collapse. NEK8 suppresses DSB formation by limiting cyclin A-associated CDK activity. Strikingly, a mutation in NEK8 that is associated with renal ciliopathies affects its genome maintenance functions. Moreover, kidneys of NEK8 mutant mice accumulate DNA damage, and loss of NEK8 or replication stress similarly disrupts renal cell architecture in a 3D-culture system. Thus, NEK8 is a critical component of the DNA damage response that links replication stress with cystic kidney disorders.
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DOI：
10.1083/jcb.200905059
发表时间：
2010-03-08
期刊：
The Journal of cell biology
影响因子：
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作者：
Beck H;Nähse V;Larsen MS;Groth P;Clancy T;Lees M;Jørgensen M;Helleday T;Syljuåsen RG;Sørensen CS
通讯作者：
Sørensen CS
影响因子：
64.8
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通讯作者：
Bartek, J
影响因子：
64.5
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Chaki M;Airik R;Ghosh AK;Giles RH;Chen R;Slaats GG;Wang H;Hurd TW;Zhou W;Cluckey A;Gee HY;Ramaswami G;Hong CJ;Hamilton BA;Cervenka I;Ganji RS;Bryja V;Arts HH;van Reeuwijk J;Oud MM;Letteboer SJ;Roepman R;Husson H;Ibraghimov-Beskrovnaya O;Yasunaga T;Walz G;Eley L;Sayer JA;Schermer B;Liebau MC;Benzing T;Le Corre S;Drummond I;Janssen S;Allen SJ;Natarajan S;O'Toole JF;Attanasio M;Saunier S;Antignac C;Koenekoop RK;Ren H;Lopez I;Nayir A;Stoetzel C;Dollfus H;Massoudi R;Gleeson JG;Andreoli SP;Doherty DG;Lindstrad A;Golzio C;Katsanis N;Pape L;Abboud EB;Al-Rajhi AA;Lewis RA;Omran H;Lee EY;Wang S;Sekiguchi JM;Saunders R;Johnson CA;Garner E;Vanselow K;Andersen JS;Shlomai J;Nurnberg G;Nurnberg P;Levy S;Smogorzewska A;Otto EA;Hildebrandt F
通讯作者：
Hildebrandt F
DOI：
10.1083/jcb.201204035
发表时间：
2012-08-06
期刊：
The Journal of cell biology
影响因子：
--
作者：
Daniel JA;Pellegrini M;Lee BS;Guo Z;Filsuf D;Belkina NV;You Z;Paull TT;Sleckman BP;Feigenbaum L;Nussenzweig A
通讯作者：
Nussenzweig A
影响因子：
16
作者：
Paulsen, Renee D.;Soni, Deena V.;Wollman, Roy;Hahn, Angela T.;Yee, Muh-Ching;Guan, Anna;Hesley, Jayne A.;Miller, Steven C.;Cromwell, Evan F.;Solow-Cordero, David E.;Meyer, Tobias;Cimprich, Karlene A.
通讯作者：
Cimprich, Karlene A.