NEK5 interacts with topoisomerase IIβ and is involved in the DNA damage response induced by etoposide

Melo‐Hanchuk, Talita Diniz; Slepicka, Priscila Ferreira; Pelegrini, Alessandra Luíza; Menck, Carlos Frederico Martins; Kobarg, Jörg

doi:10.1002/jcb.28943

Cited by 14 publications

(15 citation statements)

References 60 publications

(119 reference statements)

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“…For instance, NEK1 binds to ATR-ATRIP and promotes ATR signaling, whereas NEK11 controls the DNA damage checkpoint by directly phosphorylating and degrading Cdc25A [6,7]. NEK5 silencing increases etoposide-induced DNA damage and impairs DNA repair, whereas NEK8 has been found to involve in replication fork stability through regulating Rad51 [10,11]. All these data strongly support the notion that some of the NEK kinases are closely associated with DNA damage response and repair.…”

Section: Introductionsupporting

confidence: 54%

“…Numerous studies have revealed that the NEK kinases participate in diverse cellular functions, including cell cycle control, centrosome organization, RNA splicing, inflammation and DNA damage response [5]. Of them, NEK1, NEK4, NEK5, NEK8, NEK10 and NEK11 have been linked to the DNA damage response [6][7][8][9][10][11]. For instance, NEK1 binds to ATR-ATRIP and promotes ATR signaling, whereas NEK11 controls the DNA damage checkpoint by directly phosphorylating and degrading Cdc25A [6,7].…”

Section: Introductionmentioning

confidence: 99%

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Targeting NEK2 impairs oncogenesis and radioresistance via inhibiting the Wnt1/β-catenin signaling pathway in cervical cancer

Zeng

Shi

et al. 2020

J Exp Clin Cancer Res

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Background NEK2, a serine/threonine kinase involved in mitosis, has been found to function in chromosome instability, tumor progression and metastasis, but its role in cervical cancer radioresistance remains unknown. Methods We detected the protein levels of NEK2 in cervical carcinoma tissues and paired paracarcinoma tissues by immunohistochemistry. The roles of NEK2 in oncogenesis were examined using cell growth and colony formation assays, EdU assay, apoptosis assay as well as in vivo mouse model. γ-H2AX and Rad51 foci formation, neutral comet assay and clonogenic cell survival assay were applied to determine the radiosensitivity of cervical cancer cells. RNA-seq was performed to identify the downstream effector of NEK2. The gene expression levels were measured by Real-time PCR. Results We report that NEK2 protein level is overexpressed and correlated with the tumor stage and lymph node metastasis in cervical cancer tissues. Furthermore, we provided evidence that depletion of NEK2 impairs oncogenesis and enhances radiosensitivity in cervical cancer. Using RNA sequencing, we identify Wnt1 as a key downstream effector of NEK2. Knockdown of NEK2 downregulates the mRNA and protein levels of Wnt1, thereby inhibiting the activation of the Wnt/β-catenin signaling pathway. More importantly, the observed consequences induced by NEK2 depletion in cervical cancer cells can be partially rescued by Wnt1 overexpression. Conclusions Our results demonstrate that NEK2 activates the Wnt/β-catenin signaling pathway via Wnt1 to drive oncogenesis and radioresistance in cervical cancer, indicating that NEK2 may be a promising target for the radiosensitization of cervical cancer.

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Section: Introductionsupporting

confidence: 54%

Section: Introductionmentioning

confidence: 99%

Targeting NEK2 impairs oncogenesis and radioresistance via inhibiting the Wnt1/β-catenin signaling pathway in cervical cancer

Zeng

Shi

et al. 2020

J Exp Clin Cancer Res

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“…Our research group showed that NEK5 is also located in mitochondria, where it interacts with local proteins, such as COX11 and MTX2, and its knockdown leads to altered mitochondrial respiration and increase in ROS production [8]. Recently, we also demonstrated that NEK5 participates in nuclear DNA damage response (DDR) and interacts with topoisomerase IIβ [4], one of the only topoisomerase isoforms present in mtDNA [22].…”

Section: Figmentioning

confidence: 99%

NEK5 interacts with LonP1 and its kinase activity is essential for the regulation of mitochondrial functions and mtDNA maintenance

et al. 2021

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Little is known about Nima‐related kinase (NEKs), a widely conserved family of kinases that have key roles in cell‐cycle progression. Nevertheless, it is now clear that multiple NEK family members act in networks, not only to regulate specific events of mitosis, but also to regulate metabolic events independently of the cell cycle. NEK5 was shown to act in centrosome disjunction, caspase‐3 regulation, myogenesis, and mitochondrial respiration. Here, we demonstrate that NEK5 interacts with LonP1, an AAA+ mitochondrial protease implicated in protein quality control and mtDNA remodeling, within the mitochondria and it might be involved in the LonP1‐TFAM signaling module. Moreover, we demonstrate that NEK5 kinase activity is required for maintaining mitochondrial mass and functionality and mtDNA integrity after oxidative damage. Taken together, these results show a new role of NEK5 in the regulation of mitochondrial homeostasis and mtDNA maintenance, possibly due to its interaction with key mitochondrial proteins, such as LonP1.

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“…NEK5 was also found to regulate centrosome integrity in the interphase [21]. Most recently, NEK5 was linked to DDR and genomic stability, where it was demonstrated that it interacts with topoisomerase II β (TOPOIIβ) [32].…”

Section: Nek5mentioning

confidence: 99%

Checking NEKs: Overcoming a Bottleneck in Human Diseases

et al. 2020

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In previous years, several kinases, such as phosphoinositide 3-kinase (PI3K), mammalian target of rapamycin (mTOR), and extracellular-signal-regulated kinase (ERK), have been linked to important human diseases, although some kinase families remain neglected in terms of research, hiding their relevance to therapeutic approaches. Here, a review regarding the NEK family is presented, shedding light on important information related to NEKs and human diseases. NEKs are a large group of homologous kinases with related functions and structures that participate in several cellular processes such as the cell cycle, cell division, cilia formation, and the DNA damage response. The review of the literature points to the pivotal participation of NEKs in important human diseases, like different types of cancer, diabetes, ciliopathies and central nervous system related and inflammatory-related diseases. The different known regulatory molecular mechanisms specific to each NEK are also presented, relating to their involvement in different diseases. In addition, important information about NEKs remains to be elucidated and is highlighted in this review, showing the need for other studies and research regarding this kinase family. Therefore, the NEK family represents an important group of kinases with potential applications in the therapy of human diseases.

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NEK5 interacts with topoisomerase IIβ and is involved in the DNA damage response induced by etoposide

Cited by 14 publications

References 60 publications

Targeting NEK2 impairs oncogenesis and radioresistance via inhibiting the Wnt1/β-catenin signaling pathway in cervical cancer

Targeting NEK2 impairs oncogenesis and radioresistance via inhibiting the Wnt1/β-catenin signaling pathway in cervical cancer

NEK5 interacts with LonP1 and its kinase activity is essential for the regulation of mitochondrial functions and mtDNA maintenance

Checking NEKs: Overcoming a Bottleneck in Human Diseases

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