Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94025, USA.
Mol Cell. 2013 Aug 22;51(4):423-39. doi: 10.1016/j.molcel.2013.08.006.
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) that 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.
肾脏纤毛病是肾衰竭的一个主要原因，但它们的确切病因还不清楚。NEK8/NPHP9 是一种纤毛激酶，与人类和小鼠的两种肾脏纤毛病——肾单位肾痨（NPHP）和多囊肾病有关。在这里，我们确定 NEK8 是 ATR 介导的复制应激反应的关键效应因子。缺乏 NEK8 的细胞会自发形成 DNA 双链断裂（DSB），当复制叉停滞时，DSB 进一步积累，它们的叉速率降低、非计划起点启动和复制叉崩溃增加。NEK8 通过限制细胞周期蛋白 A 相关 CDK 活性来抑制 DSB 的形成。引人注目的是，与肾脏纤毛病相关的 NEK8 突变会影响其基因组维护功能。此外，NEK8 突变小鼠的肾脏会积累 DNA 损伤，而 NEK8 或复制应激的缺失也会在 3D 培养系统中类似地破坏肾脏细胞结构。因此，NEK8 是 DNA 损伤反应的关键组成部分，它将复制应激与囊性肾脏疾病联系起来。
