Nek1 silencing slows down DNA repair and blocks DNA damage-induced cell cycle arrest

Pelegrini, Alessandra Luíza; Moura, Dinara Jaqueline; Brenner, B.; Ledur, Pítia Flores; Maques, Gabriela Porto; Henriques, João Antônio Pêgas; Saffi, Jenifer; Lenz, Guido

doi:10.1093/mutage/geq026

Cited by 63 publications

(61 citation statements)

References 31 publications

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“…Whereas some NEKs, such as NEK2 and NEK6, are checkpoint targets that are inhibited by DNA damage (Fletcher et al, 2004;Lee et al, 2008), others have more integral roles in DNA-damageresponse (DDR) signalling. NEK1 is involved in both the sensing and the repair of DNA strand breaks at the G1-S and G2-M transitions (Chen et al, 2011;Chen et al, 2008;Pelegrini et al, 2010;Polci et al, 2004). Depleting cells of NEK1 causes failure of checkpoint kinase 1 and 2 (CHK1 and CHK2; also known as CHEK1 and CHEK2) activation in response to ultraviolet (UV) light and ionising radiation (IR), which places NEK1 early in this pathway.…”

Section: The Role Of Neks In Cell Cycle Checkpointsmentioning

confidence: 99%

Cell cycle regulation by the NEK family of protein kinases

Fry

O’Regan

Sabir

et al. 2012

Journal of Cell Science

308

322

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SummaryGenetic screens for cell division cycle mutants in the filamentous fungus Aspergillus nidulans led to the discovery of never-in-mitosis A (NIMA), a serine/threonine kinase that is required for mitotic entry. Since that discovery, NIMA-related kinases, or NEKs, have been identified in most eukaryotes, including humans where eleven genetically distinct proteins named NEK1 to NEK11 are expressed. Although there is no evidence that human NEKs are essential for mitotic entry, it is clear that several NEK family members have important roles in cell cycle control. In particular, NEK2, NEK6, NEK7 and NEK9 contribute to the establishment of the microtubulebased mitotic spindle, whereas NEK1, NEK10 and NEK11 have been implicated in the DNA damage response. Roles for NEKs in other aspects of mitotic progression, such as chromatin condensation, nuclear envelope breakdown, spindle assembly checkpoint signalling and cytokinesis have also been proposed. Interestingly, NEK1 and NEK8 also function within cilia, the microtubule-based structures that are nucleated from basal bodies. This has led to the current hypothesis that NEKs have evolved to coordinate microtubule-dependent processes in both dividing and non-dividing cells. Here, we review the functions of the human NEKs, with particular emphasis on those family members that are involved in cell cycle control, and consider their potential as therapeutic targets in cancer.

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Section: The Role Of Neks In Cell Cycle Checkpointsmentioning

confidence: 99%

Cell cycle regulation by the NEK family of protein kinases

Fry

O’Regan

Sabir

et al. 2012

Journal of Cell Science

308

322

View full text Add to dashboard Cite

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“…Interestingly, several members of the Nek family have been linked to the ATR-mediated DNA damage response. Nek1, through unknown mechanisms, promotes Chk1 activation (22,23) and repair of several types of DNA damage (24). Nek11, on the other hand, is a substrate of Chk1, and it promotes the G2/M checkpoint arrest by phosphorylating Cdc25A (cell division cycle 25A) and targeting Cdc25A for degradation (25).…”

mentioning

confidence: 99%

Nek1 kinase associates with ATR–ATRIP and primes ATR for efficient DNA damage signaling

Liu

Ouyang

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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The master checkpoint kinase ATR (ATM and Rad3-related) and its partner ATRIP (ATR-interacting protein) exist as a complex and function together in the DNA damage response. Unexpectedly, we found that the stability of the ATR-ATRIP complex is regulated by an unknown kinase independently of DNA damage. In search for this regulator of ATR-ATRIP, we found that a single member of the NIMA (never in mitosis A)-related kinase family, Nek1, is critical for initiating the ATR response. Upon DNA damage, cells lacking Nek1 failed to efficiently phosphorylate multiple ATR substrates and support ATR autophosphorylation at threnine 1989, one of the earliest events during the ATR response. The ability of Nek1 to promote ATR activation relies on the kinase activity of Nek1 and its interaction with ATR-ATRIP. Importantly, even in undamaged cells, Nek1 is required for maintaining the levels of ATRIP, the association between ATR and ATRIP, and the basal kinase activity of ATR. Thus, as an ATR-associated kinase, Nek1, enhances the stability and activity of ATR-ATRIP before DNA damage, priming ATR-ATRIP for a robust DNA damage response.

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“…Finally, two cytoskeletal kinases were also identified (Ack1 and Pak1), along with DDR2, which was previously shown to localize in focal adhesions (12). A set of kinases previously known for important roles in cell growth or cell cycle was also identified to affect cell migration (Cdk2, Nek1, and Nek11) (13)(14)(15).…”

Section: Figmentioning

confidence: 91%

Exploiting polypharmacology for drug target deconvolution

Gujral

Peshkin

Kirschner

2014

Proc. Natl. Acad. Sci. U.S.A.

106

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Polypharmacology (action of drugs against multiple targets) represents a tempting avenue for new drug development; unfortunately, methods capable of exploiting the known polypharmacology of drugs for target deconvolution are lacking. Here, we present an ensemble approach using elastic net regularization combined with mRNA expression profiling and previously characterized data on a large set of kinase inhibitors to identify kinases that are important for epithelial and mesenchymal cell migration. By profiling a selected optimal set of 32 kinase inhibitors in a panel against six cell lines, we identified cell type-specific kinases that regulate cell migration. Our discovery of several informative kinases with a previously uncharacterized role in cell migration (such as Mst and Taok family of MAPK kinases in mesenchymal cells) may represent novel targets that warrant further investigation. Target deconvolution using our ensemble approach has the potential to aid in the rational design of more potent but less toxic drug combinations.systems pharmacology | regularized regression | perturbation biology | predictive modeling | cancer cell migration F or most diseases, the development of specific "one target, one drug" or euphemistically, "magic bullet" therapy, has been difficult to achieve (1). It is even rather difficult to chemically achieve single target specificity. Furthermore, it is now evident that many of the most effective drugs in therapeutic areas as diverse as oncology (such as Gleevec), psychiatry (such as serotonin reuptake inhibitors), and inflammation (such as aspirin) act on multiple rather than single targets-a phenomenon known as polypharmacology (2, 3). Although the pharmaceutical industry and the US Food and Drug Administration (FDA) has for years focused on single targets, it may turn out to be true that hitting multiple targets is preferable, an emerging idea referred to as network pharmacology.Designing drugs with a specific multitarget profile or designing a rational combination of such drugs is both complex and difficult, but could serve to improve the balance between efficacy and safety compared with single targets agents. Therefore, despite the complexity of designing such drugs, there is an incentive to develop new systems-based methods capable of exploiting the known polypharmacology of drugs to identify the molecular targets of active hits, also called "target deconvolution." Such methods are not only important for elucidating mechanisms of action but also for identifying effective pathways involved in disease as a preliminary step in rational design of drugs for new targets. Furthermore, if target-specific toxicity and off-target effects could be addressed early in the drug discovery pipeline, the high attrition rate in drug development might be reduced (4).Recent advances in high-throughput "omics" technologies have led to the development of methods to efficiently and reliably profile drug target selectivities both in vitro and in the cellular environment. One such well-characterized s...

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Nek1 silencing slows down DNA repair and blocks DNA damage-induced cell cycle arrest

Cited by 63 publications

References 31 publications

Cell cycle regulation by the NEK family of protein kinases

Cell cycle regulation by the NEK family of protein kinases

Nek1 kinase associates with ATR–ATRIP and primes ATR for efficient DNA damage signaling

Exploiting polypharmacology for drug target deconvolution

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