2013
DOI: 10.1016/j.molcel.2013.08.006
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NEK8 Links the ATR-Regulated Replication Stress Response and S Phase CDK Activity to Renal Ciliopathies

Abstract: Summary 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, unsched… Show more

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Cited by 125 publications
(164 citation statements)
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“…Interestingly, several of these are either known, or putative, substrates for the key DDR regulating kinases ATM and ATR (Matsuoka et al, 2007;Smith et al, 2009), which might point to DDR-related regulation of these proteins. Collectively, these findings, together with recent genetic studies Choi et al, 2013;Kalay et al, 2011;Sivasubramaniam et al, 2008;Stiff et al, 2013;Valdés-Sánchez et al, 2013;Zhou et al, 2012), highlight emerging functional links between centrosomal satellites, the DNA damage response, genome stability and human ciliopathies (Chavali and Gergely, 2013). These findings open up new exciting avenues of research and suggest that mutations in other DDR-related proteins might be causal for a subset of human ciliopathies, and that, potentially, mutations in some centrosomal satellite proteins might be causal for a subset of cancer predisposition disorders.…”
Section: Discussionsupporting
confidence: 60%
See 1 more Smart Citation
“…Interestingly, several of these are either known, or putative, substrates for the key DDR regulating kinases ATM and ATR (Matsuoka et al, 2007;Smith et al, 2009), which might point to DDR-related regulation of these proteins. Collectively, these findings, together with recent genetic studies Choi et al, 2013;Kalay et al, 2011;Sivasubramaniam et al, 2008;Stiff et al, 2013;Valdés-Sánchez et al, 2013;Zhou et al, 2012), highlight emerging functional links between centrosomal satellites, the DNA damage response, genome stability and human ciliopathies (Chavali and Gergely, 2013). These findings open up new exciting avenues of research and suggest that mutations in other DDR-related proteins might be causal for a subset of human ciliopathies, and that, potentially, mutations in some centrosomal satellite proteins might be causal for a subset of cancer predisposition disorders.…”
Section: Discussionsupporting
confidence: 60%
“…Interestingly, the DDR kinase ATR has been shown recently to localise to the photoreceptor connecting cilium, and ATRdeficient mice exhibit ciliary defects and photoreceptor degeneration (Valdés-Sánchez et al, 2013). Furthermore, it has been demonstrated recently that the renal-ciliopathy-associated kinase Nek8 also plays a role in ATR signalling during the cellular responses to replication stress (Choi et al, 2013). Finally, mutations in several DNA replication factors impair ciliogenesis and are causative of Meier-Gorlin syndrome (Stiff et al, 2013).…”
Section: Introductionmentioning
confidence: 99%
“…Furthermore, γ-H2AX was apparent in CECs of LPK kidneys throughout the time-course of disease. Given that the LPK rat possesses a mutation in Nek8 [28] , and abnormalities in this gene lead to DNA double-strand breaks (DSBs) and abnormal structuring of epithelial cells in 3D spheroid cultures [36] , our data add credence to the theory that Nek8-linked DNA damage is involved in the pathogenesis of renal ciliopathies and renal cystic diseases [48] . Interestingly, γ-H2AX was strongly expressed at week 1 in LPK kidneys, when the expression of NF-κB proteins was low ( Figure 14).…”
supporting
confidence: 61%
“…Previous studies in Nek8 mice revealed that DNA damage is evident early in diseased animals with this mutation [36] . Therefore, to elucidate whether there is a relationship between NF-κB activation and DNA damage, we assessed the expression of a phosphorylated histone H2A variant, γ-H2AX, which is produced during double-strand DNA breakage [37] .…”
Section: γ -H2ax Expression In Experimental and Human Pkd Kidneysmentioning
confidence: 92%
“…One possibility is that CEP290 acts in a manner similar that of the other ciliary proteins mutated in renal ciliopathies (CEP164, ZNF423, SDCCAG8, NEK8), which have been associated with enhanced DDR signaling (14)(15)(16). A single study examining the events leading to DNA damage in this setting recently established a role for NEK8 in the ATR-regulated replication stress response and in the regulation S-phase cyclin-dependent kinase (CDK) activity (16). However, only three families with mutations in NEK8 have been described (17), making these data less clinically relevant.…”
Section: Introductionmentioning
confidence: 99%