On Broken Ne(c)ks and Broken DNA: The Role of Human NEKs in the DNA Damage Response

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...

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Published inCells (Basel, Switzerland) Vol. 10; no. 3; p. 507
Main Authors Pavan, Isadora Carolina Betim, Peres de Oliveira, Andressa, Dias, Pedro Rafael Firmino, Basei, Fernanda Luisa, Issayama, Luidy Kazuo, Ferezin, Camila de Castro, Silva, Fernando Riback, Rodrigues de Oliveira, Ana Luisa, Alves Dos Reis Moura, Lívia, Martins, Mariana Bonjiorno, Simabuco, Fernando Moreira, Kobarg, Jörg
Format Journal Article
LanguageEnglish
Published Switzerland MDPI AG 27.02.2021
MDPI
Subjects
Apoptosis
Ataxia telangiectasia
Ataxia telangiectasia mutated protein
Cell activation
Cell cycle
Cell division
Chromosomes
Cilia
Cyclin-dependent kinases
Deoxyribonucleic acid
DNA
DNA damage
DNA Damage - genetics
DNA damage response
DNA repair
DNA Repair - genetics
DNA-dependent protein kinase
Double-strand break repair
Gene expression
Genomes
Homology
Humans
kinase
Kinases
Metabolism
Mitosis
Nek1 protein
Non-homologous end joining
p53 Protein
Phosphorylation
Protein interaction
protein kinase
Proteins
Review
kinase
DNA damage response
cell cycle
protein kinase
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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.
AbstractList 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.
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.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.
Author Simabuco, Fernando Moreira
Peres de Oliveira, Andressa
Issayama, Luidy Kazuo
Basei, Fernanda Luisa
Alves Dos Reis Moura, Lívia
Rodrigues de Oliveira, Ana Luisa
Kobarg, Jörg
Dias, Pedro Rafael Firmino
Pavan, Isadora Carolina Betim
Martins, Mariana Bonjiorno
Ferezin, Camila de Castro
Silva, Fernando Riback
AuthorAffiliation 1 Graduate Program in “Ciências Farmacêuticas”, School of Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, State University of Campinas (UNICAMP), R. Cândido Portinari 200, Prédio 2, Campinas CEP 13083-871, Brazil; isadora.bpavan@gmail.com (I.C.B.P.); andressa2401@gmail.com (A.P.d.O.); pedrofirminodias@gmail.com (P.R.F.D.); fernandabasei@gmail.com (F.L.B.); kazuo.bio@gmail.com (L.K.I.); fernandoriback@hotmail.com (F.R.S.); aluisa1702@gmail.com (A.L.R.d.O.); l156284@dac.unicamp.br (L.A.d.R.M.); mbonjiorno@gmail.com (M.B.M.)
2 Graduate Program in “Biologia Funcional e Molecular”, Department of Biochemistry and Tissue Biology, Institute of Biology, State University of Campinas (UNICAMP), Campinas 13083-857, Brazil; camilaferezin7@gmail.com
3 School of Applied Sciences, State University of Campinas (UNICAMP), Limeira CEP 13484-350, Brazil; simabuco@gmail.com
AuthorAffiliation_xml – name: 1 Graduate Program in “Ciências Farmacêuticas”, School of Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, State University of Campinas (UNICAMP), R. Cândido Portinari 200, Prédio 2, Campinas CEP 13083-871, Brazil; isadora.bpavan@gmail.com (I.C.B.P.); andressa2401@gmail.com (A.P.d.O.); pedrofirminodias@gmail.com (P.R.F.D.); fernandabasei@gmail.com (F.L.B.); kazuo.bio@gmail.com (L.K.I.); fernandoriback@hotmail.com (F.R.S.); aluisa1702@gmail.com (A.L.R.d.O.); l156284@dac.unicamp.br (L.A.d.R.M.); mbonjiorno@gmail.com (M.B.M.)
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/33673578$$D View this record in MEDLINE/PubMed
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2021 by the authors. 2021
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Issue 3
Keywords kinase
DNA damage response
cell cycle
protein kinase
Language English
License Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
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These authors contributed equally to this work.
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Snippet 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...
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StartPage 507
SubjectTerms Apoptosis
Ataxia telangiectasia
Ataxia telangiectasia mutated protein
Cell activation
Cell cycle
Cell division
Chromosomes
Cilia
Cyclin-dependent kinases
Deoxyribonucleic acid
DNA
DNA damage
DNA Damage - genetics
DNA damage response
DNA repair
DNA Repair - genetics
DNA-dependent protein kinase
Double-strand break repair
Gene expression
Genomes
Homology
Humans
kinase
Kinases
Metabolism
Mitosis
Nek1 protein
Non-homologous end joining
p53 Protein
Phosphorylation
Protein interaction
protein kinase
Proteins
Review
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Title On Broken Ne(c)ks and Broken DNA: The Role of Human NEKs in the DNA Damage Response
URI https://www.ncbi.nlm.nih.gov/pubmed/33673578
https://www.proquest.com/docview/2497030234
https://www.proquest.com/docview/2498486754/abstract/
https://pubmed.ncbi.nlm.nih.gov/PMC7997185
https://doaj.org/article/3656be30a566449698c626134c7f279e
Volume 10
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