Abstract
NIMA-related kinases, or NEKs, are a family of Ser/Thr protein kinases involved in cell cycle and mitosis, centrosome disjunction, primary cilia functions, and DNA damage responses among other biological functional contexts in vertebrate cells. In human cells, there are 11 members, termed NEK1 to 11, and the research has mainly focused on exploring the more predominant roles of NEKs in mitosis regulation and cell cycle. A possible important role of NEKs in DNA damage response (DDR) first emerged for NEK1, but recent studies for most NEKs showed participation in DDR. A detailed analysis of the protein interactions, phosphorylation events, and studies of functional aspects of NEKs from the literature led us to propose a more general role of NEKs in DDR. In this review, we express that NEK1 is an activator of ataxia telangiectasia and Rad3-related (ATR), and its activation results in cell cycle arrest, guaranteeing DNA repair while activating specific repair pathways such as homology repair (HR) and DNA double-strand break (DSB) repair. For NEK2, 6, 8, 9, and 11, we found a role downstream of ATR and ataxia telangiectasia mutated (ATM) that results in cell cycle arrest, but details of possible activated repair pathways are still being investigated. NEK4 shows a connection to the regulation of the nonhomologous end-joining (NHEJ) repair of DNA DSBs, through recruitment of DNA-PK to DNA damage foci. NEK5 interacts with topoisomerase IIβ, and its knockdown results in the accumulation of damaged DNA. NEK7 has a regulatory role in the detection of oxidative damage to telomeric DNA. Finally, NEK10 has recently been shown to phosphorylate p53 at Y327, promoting cell cycle arrest after exposure to DNA damaging agents. In summary, this review highlights important discoveries of the ever-growing involvement of NEK kinases in the DDR pathways. A better understanding of these roles may open new diagnostic possibilities or pharmaceutical interventions regarding the chemo-sensitizing inhibition of NEKs in various forms of cancer and other diseases.
Highlights
Human NEKs (never in mitosis A (NIMA)-related kinases) are a family of protein kinases composed of 11 members that share structural homology with Aspergillus nidulansNIMA proteins [1,2]
Topoisomerase IIβ is normally present uniformly throughout the cell cycle and it may sustain a catenated state of sister chromosomes to assist chromosome condensation and cohesion without subsequently interfering with segregation [134]. Those data indicate that NEK5 might interact with topoisomerase IIβ to halt the cell cycle upon DNA damage, as this interaction is increased in the early response to damage, leading cells to arrest at the G2/M checkpoint, this hypothesis should be further explored
In the presence of genotoxic stress caused by cisplatin, the lack of NEK10 impaired the induction of p21 and, upon ionizing radiation (IR), the levels of p21 increased in control cells compared to NEK10 knocked-down cells [183]
Summary
Human NEKs (never in mitosis A (NIMA)-related kinases) are a family of protein kinases composed of 11 members that share structural homology with Aspergillus nidulans. The p53 protein, a tumor suppressor, plays a crucial role in DDR by regulating a large number of genes, related to DNA damage repair, cell cycle arrest, apoptosis, and senescence [34,35]. Those data indicate that NEK5 might interact with topoisomerase IIβ to halt the cell cycle upon DNA damage, as this interaction is increased in the early response to damage, leading cells to arrest at the G2/M checkpoint, this hypothesis should be further explored Another NEK5 interactor related to DDR is Bcl-2-associated transcription factor 1. Since NEK5 has been related to both apoptosis and DDR processes, and the roles of BCLAF1 are based on whether cells will correct the DNA damage or undergo senescence or apoptosis, more experiments are needed to better understand the relationship between these two proteins. Caffeine is a known inhibitor of the ATM/ATR-Chk1/Chk signaling [141] (Figure 3)
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