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, 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.

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Single v dual knockdowns of the chromatin remodeling ATPase, SNF2L and its isoform, SNF2LT have similar effects on DNA damage but opposite effects on the DNA damage response, cell cycle arrest and apoptosis

The FASEB Journal ◽

10.1096/fasebj.24.1_supplement.421.2 ◽

2010 ◽

Vol 24 (S1) ◽

Author(s):

Sanford H Barsky ◽

Yi Xiao ◽

Kurtis Yearsley ◽

Yin Ye

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Cell Cycle Arrest ◽

Chromatin Remodeling ◽

Dna Damage Response ◽

Cycle Arrest ◽

Damage Response

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RUNX Family Participates in the Regulation of p53-Dependent DNA Damage Response

International Journal of Genomics ◽

10.1155/2013/271347 ◽

2013 ◽

Vol 2013 ◽

pp. 1-12 ◽

Cited By ~ 22

Author(s):

Toshinori Ozaki ◽

Akira Nakagawara ◽

Hiroki Nagase

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Cell Death ◽

Cell Cycle Arrest ◽

Dna Damage Response ◽

Apoptotic Cell ◽

Genetic Alterations ◽

Apoptotic Cell Death ◽

Cycle Arrest ◽

Damage Response

A proper DNA damage response (DDR), which monitors and maintains the genomic integrity, has been considered to be a critical barrier against genetic alterations to prevent tumor initiation and progression. The representative tumor suppressor p53 plays an important role in the regulation of DNA damage response. When cells receive DNA damage, p53 is quickly activated and induces cell cycle arrest and/or apoptotic cell death through transactivating its target genes implicated in the promotion of cell cycle arrest and/or apoptotic cell death such asp21WAF1,BAX, andPUMA. Accumulating evidence strongly suggests that DNA damage-mediated activation as well as induction of p53 is regulated by posttranslational modifications and also by protein-protein interaction. Loss of p53 activity confers growth advantage and ensures survival in cancer cells by inhibiting apoptotic response required for tumor suppression. RUNX family, which is composed of RUNX1, RUNX2, and RUNX3, is a sequence-specific transcription factor and is closely involved in a variety of cellular processes including development, differentiation, and/or tumorigenesis. In this review, we describe a background of p53 and a functional collaboration between p53 and RUNX family in response to DNA damage.

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Inhibition of p53 improves CRISPR/Cas - mediated precision genome editing

10.1101/180943 ◽

2017 ◽

Cited By ~ 2

Author(s):

Emma Haapaniemi ◽

Sandeep Botla ◽

Jenna Persson ◽

Bernhard Schmierer ◽

Jussi Taipale

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Homologous Recombination ◽

Cell Cycle Arrest ◽

Genome Editing ◽

Dna Damage Response ◽

Normal Cells ◽

Cycle Arrest ◽

Damage Response

AbstractWe report here that genome editing by CRISPR/Cas9 induces a p53-mediated DNA damage response and cell cycle arrest. Transient inhibition of p53 prevents this response, and increases the rate of homologous recombination more than five-fold. This provides a way to improve precision genome editing of normal cells, but warrants caution in using CRISPR for human therapies until the mechanism of the activation of p53 is elucidated.

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Faculty Opinions recommendation of The oxygen-rich postnatal environment induces cardiomyocyte cell-cycle arrest through DNA damage response.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718363633.793495805 ◽

2014 ◽

Author(s):

Christian Mühlfeld

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Cell Cycle Arrest ◽

Dna Damage Response ◽

Cycle Arrest ◽

Damage Response ◽

Postnatal Environment

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The Oxygen-Rich Postnatal Environment Induces Cardiomyocyte Cell-Cycle Arrest through DNA Damage Response

Cell ◽

10.1016/j.cell.2014.03.032 ◽

2014 ◽

Vol 157 (3) ◽

pp. 565-579 ◽

Cited By ~ 349

Author(s):

Bao N. Puente ◽

Wataru Kimura ◽

Shalini A. Muralidhar ◽

Jesung Moon ◽

James F. Amatruda ◽

...

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Cell Cycle Arrest ◽

Dna Damage Response ◽

Cycle Arrest ◽

Damage Response ◽

Postnatal Environment

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Human Parvovirus B19 DNA Replication Induces a DNA Damage Response That Is Dispensable for Cell Cycle Arrest at Phase G2/M

Journal of Virology ◽

10.1128/jvi.01007-12 ◽

2012 ◽

Vol 86 (19) ◽

pp. 10748-10758 ◽

Cited By ~ 28

Author(s):

S. Lou ◽

Y. Luo ◽

F. Cheng ◽

Q. Huang ◽

W. Shen ◽

...

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Dna Replication ◽

Cell Cycle Arrest ◽

Dna Damage Response ◽

Parvovirus B19 ◽

Human Parvovirus B19 ◽

Cycle Arrest ◽

Damage Response

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ATM: Main Features, Signaling Pathways, and Its Diverse Roles in DNA Damage Response, Tumor Suppression, and Cancer Development

Genes ◽

10.3390/genes12060845 ◽

2021 ◽

Vol 12 (6) ◽

pp. 845

Author(s):

Liem Minh Phan ◽

Abdol-Hossein Rezaeian

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Cell Cycle Arrest ◽

Signaling Pathways ◽

Dna Damage Response ◽

Cancer Development ◽

Cellular Processes ◽

Cycle Arrest ◽

Damage Response ◽

Cancer Cell Survival

ATM is among of the most critical initiators and coordinators of the DNA-damage response. ATM canonical and non-canonical signaling pathways involve hundreds of downstream targets that control many important cellular processes such as DNA damage repair, apoptosis, cell cycle arrest, metabolism, proliferation, oxidative sensing, among others. Of note, ATM is often considered a major tumor suppressor because of its ability to induce apoptosis and cell cycle arrest. However, in some advanced stage tumor cells, ATM signaling is increased and confers remarkable advantages for cancer cell survival, resistance to radiation and chemotherapy, biosynthesis, proliferation, and metastasis. This review focuses on addressing major characteristics, signaling pathways and especially the diverse roles of ATM in cellular homeostasis and cancer development.

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What Lies in between Telomere and Organismal Ageing: Comparison between Replicative Senescence and Stress-Induced Premature Senescence

E3S Web of Conferences ◽

10.1051/e3sconf/202124503051 ◽

2021 ◽

Vol 245 ◽

pp. 03051

Author(s):

Hanyi Jia

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Cell Cycle Arrest ◽

Dna Damage Response ◽

Replicative Senescence ◽

Premature Senescence ◽

Cycle Arrest ◽

Damage Response ◽

Permanent Cell ◽

Stress Induced Premature Senescence

A mitotic cell that rests in permanent cell cycle arrest without the ability to divide is considered as a senescent cell. Cellular senescence is essential to limit the function of cells with heavy DNA damages. The lack of senescence is in favour of tumorigenesis, whereas the accumulation of senescent cells in tissues is likely to induce ageing and age-related pathologies on the organismal level. Understanding of cellular senescence is thus critical to both cancer and ageing studies. Senescence, essentially permanent cell cycle arrest, is one of the results of DNA damage response, such as the ataxia telangiectasia mutated and the ataxia telangiectasia and Rad3-related signaling pathways. In other cases, mild DNA damages can usually be repaired after DNA damage response, while the cells with heavy damages on DNA end in apoptosis. The damage to the special structure of telomere, however, prone to result in permanent cell cycle arrest after activation of DNA damage response. In fact, a few previous pieces of research on ageing have largely focused on telomere and considered it a primary contributor to different types of senescence. For instance, its reduction in length after each replication turns on a timer for replicative senescence, and its tandem repeats specific to binding proteins makes it susceptible to DNA damage from oxidative stress, and thus stress-induced premature senescence. In most of the senescent cells, the accumulation of biomarkers is found around the telomere which has either its tail structure disassembled or damage foci exposed on the tandem repeats. In this review, among several types of senescence, I will investigate two of the most common and widely discussed types in eukaryotic cells -replicative senescence and stress-induced premature senescence - in terms of their mechanism, relationship with telomere, and implication to organismal ageing.

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Cytokinesis failure in RhoA-deficient mouse erythroblasts involves actomyosin and midbody dysregulation and triggers p53 activation

Blood ◽

10.1182/blood-2014-12-616169 ◽

2015 ◽

Vol 126 (12) ◽

pp. 1473-1482 ◽

Cited By ~ 12

Author(s):

Diamantis G. Konstantinidis ◽

Katie M. Giger ◽

Mary Risinger ◽

Suvarnamala Pushkaran ◽

Ping Zhou ◽

...

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Cell Cycle Arrest ◽

Dna Damage Response ◽

Deficient Mouse ◽

Cycle Arrest ◽

Rhoa Gtpase ◽

Key Points ◽

Damage Response ◽

P53 Activation

Key Points RhoA GTPase activates pMRLC and localizes to the site of midbody formation to regulate erythroblast cytokinesis. Cytokinesis failure in erythroblasts caused by RhoA deficiency triggers p53-mediated DNA-damage response, cell-cycle arrest, and apoptosis.

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