Regulation of the cell cycle following DNA damage in normal and Ataxia telangiectasia cells

1996 ◽  
Vol 52 (4) ◽  
pp. 316-328 ◽  
Author(s):  
H. D. Lohrer
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Ataxia Telangiectasia

scholarly journals Ataxia-telangiectasia Mutated Kinase (ATM) as a Central Regulator of Radiation-induced DNA Damage Response

2010 ◽  
Vol 53 (1) ◽  
pp. 13-17 ◽  
Author(s):  
Aleš Tichý ◽  
Jiřina Vávrová ◽  
Jaroslav Pejchal ◽  
Martina Řezáčová
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Dna Repair ◽  
Protein Kinase ◽  
Dna Damage Response ◽  
Ataxia Telangiectasia ◽  
Ataxia Telangiectasia Mutated ◽  
Damage Response ◽  
Radiation Induced ◽  
Inducible Protein

Ataxia-telangiectasia mutated kinase (ATM) is a DNA damage-inducible protein kinase, which phosphorylates plethora of substrates participating in DNA damage response. ATM significance for the cell faith is undeniable, since it regulates DNA repair, cell-cycle progress, and apoptosis. Here we describe its main signalling targets and discuss its importance in DNA repair as well as novel findings linked to this key regulatory enzyme in the terms of ionizing radiationinduced DNA damage.

scholarly journals DNA Damage-Induced Cell Cycle Regulation and Function of Novel Chk2 Phosphoresidues

2006 ◽  
Vol 26 (21) ◽  
pp. 7832-7845 ◽  
Author(s):  
Giacomo Buscemi ◽  
Luigi Carlessi ◽  
Laura Zannini ◽  
Sofia Lisanti ◽  
Enrico Fontanella ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Ataxia Telangiectasia ◽  
Dna Double Strand Breaks ◽  
Independent Manner ◽  
Strand Breaks ◽  
Cycle Arrest ◽  
And Function ◽  
Cycle Regulation

ABSTRACT Chk2 kinase is activated by DNA damage to regulate cell cycle arrest, DNA repair, and apoptosis. Phosphorylation of Chk2 in vivo by ataxia telangiectasia-mutated (ATM) on threonine 68 (T68) initiates a phosphorylation cascade that promotes the full activity of Chk2. We identified three serine residues (S19, S33, and S35) on Chk2 that became phosphorylated in vivo rapidly and exclusively in response to ionizing radiation (IR)-induced DNA double-strand breaks in an ATM- and Nbs1-dependent but ataxia telangiectasia- and Rad3-related-independent manner. Phosphorylation of these residues, restricted to the G1 phase of the cell cycle, was induced by a higher dose of IR (>1 Gy) than that required for phosphorylation of T68 (0.25 Gy) and declined by 45 to 90 min, concomitant with a rise in Chk2 autophosphorylation. Compared to the wild-type form, Chk2 with alanine substitutions at S19, S33, and S35 (Chk2S3A) showed impaired dimerization, defective auto- and trans-phosphorylation activities, and reduced ability to promote degradation of Hdmx, a phosphorylation target of Chk2 and regulator of p53 activity. Besides, Chk2S3A failed to inhibit cell growth and, in response to IR, to arrest G1/S progression. These findings underscore the critical roles of S19, S33, and S35 and argue that these phosphoresidues may serve to fine-tune the ATM-dependent response of Chk2 to increasing amounts of DNA damage.

Effects of low dose ionizing radiation on DNA damage-caused pathways by reverse-phase protein array and Bayesian networks

2017 ◽  
Vol 15 (02) ◽  
pp. 1750006 ◽  
Author(s):  
Dong-Chul Kim ◽  
Mingon Kang ◽  
Ashis Biswas ◽  
Chin-Rang Yang ◽  
Xiaoyu Wang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Bayesian Networks ◽  
Signaling Pathways ◽  
Ataxia Telangiectasia ◽  
Low Dose ◽  
Score Function ◽  
Reverse Phase Protein Array ◽  
Reverse Phase ◽  
Phase Protein

Ionizing radiation (IR) causing damages to Deoxyribonucleic acid (DNA) constitutes a broad range of base damage and double strand break, and thereby, it induces the operation of relevant signaling pathways such as DNA repair, cell cycle control, and cell apoptosis. The goal of this paper is to study how the exposure to low dose radiation affects the human body by observing the signaling pathway associated with Ataxia Telangiectasia mutated (ATM) using Reverse-Phase Protein Array (RPPA) and isogenic human Ataxia Telangiectasia (A-T) cells under different amounts and durations of IR exposure. In order to verify which proteins could be involved in a DNA damage-caused pathway, only proteins that highly interact with each other under IR are selected by using correlation coefficient. The pathway inference is derived from learning Bayesian networks in combination with prior knowledge such as Protein–Protein Interactions (PPIs) and signaling pathways from well-known databases. Learning Bayesian networks is based on a score and search scheme that provides the highest scored network structure given a score function, and the prior knowledge is included in the score function as a prior probability by using Dempster–Shafer theory (DST). In this way, the inferred network can be more likely to be similar to already discovered pathways and consistent with confirmed PPIs for more reliable inference. The experimental results show which proteins are involved in signaling pathways under IR, how the inferred pathways are different under low and high doses of IR, and how the selected proteins regulate each other in the inferred pathways. As our main contribution, overall results confirm that low dose IR could cause DNA damage and thereby induce and affect related signaling pathways such as apoptosis, cell cycle, and DNA repair.

ZnO nanoparticles-associated mitochondrial stress-induced apoptosis and G2/M arrest in HaCaT cells: a mechanistic approach

Mutagenesis ◽  
2019 ◽  
Vol 34 (3) ◽  
pp. 265-277 ◽  
Author(s):  
N V Srikanth Vallabani ◽  
Souvik Sengupta ◽  
Ritesh Kumar Shukla ◽  
Ashutosh Kumar
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Death ◽  
Ataxia Telangiectasia ◽  
Micronucleus Assay ◽  
Double Strand Breaks ◽  
Zno Nps ◽  
Strand Breaks ◽  
Mechanistic Approach ◽  
Wide Range

Abstract Zinc oxide nanoparticles (ZnO NPs) with their wide range of consumer applications in day-to-day life received great attention to evaluate their effects in humans. This study has been attempted to elucidate the DNA damage response mechanism in a dermal model exposed to ZnO NPs through Ataxia Telangiectasia Mutated (ATM)-mediated ChK1-dependent G2/M arrest. Further, viability parameters and mechanism involved in the cell death with special reference to the consequences arising due to DNA damage were explored. Our study showed that ZnO NPs at concentrations 5 and 10 µg/ml induced significant cytotoxic effect in skin cell line. Moreover, the results confirmed generation of reactive oxygen species (ROS) induces the cell death by genotoxic insult, leading to mitochondrial membrane depolarisation and cell cycle arrest. Subsequently, ZnO NPs treatment created DNA damage as confirmed via Comet assay (increase in olive tail moment), micronucleus assay (increase in micronucleus formation), double-strand breaks (increase in ATM and Ataxia Telangiectasia and Rad3 related (ATR) expression), DNA fragmentation and cell cycle (G2/M arrest) studies. Finally, marker proteins analysis concluded the mechanistic approach by demonstrating the key marker expressions HMOX1 and HSP60 (for oxidative stress), cytochrome c, APAF1, BAX, Caspase 9, Caspase 3 and decrease in BCL2 (for activating apoptotic pathway), pATM, ATR and γH2AX (for double-strand breaks), DNA-PK (involved in DNA repair) and decrease in cell cycle regulators. In together, our data revealed the mechanism of ROS generation that triggers apoptosis and DNA damage in HaCaT cell lines exposed to ZnO NPs.

scholarly journals Phosphorylation of Serine 18 Regulates Distinct p53 Functions in Mice

2004 ◽  
Vol 24 (3) ◽  
pp. 976-984 ◽  
Author(s):  
Hayla K. Sluss ◽  
Heather Armata ◽  
Judy Gallant ◽  
Stephen N. Jones
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Complex Formation ◽  
Ataxia Telangiectasia ◽  
P53 Protein ◽  
Growth Arrest ◽  
Embryonic Fibroblasts ◽  
Cycle Arrest ◽  
Oncogene Activation ◽  
Dependent Growth

ABSTRACT The p53 protein acts a tumor suppressor by inducing cell cycle arrest and apoptosis in response to DNA damage or oncogene activation. Recently, it has been proposed that phosphorylation of serine 15 in human p53 by ATM (mutated in ataxia telangiectasia) kinase induces p53 activity by interfering with the Mdm2-p53 complex formation and inhibiting Mdm2-mediated destabilization of p53. Serine 18 in murine p53 has been implicated in mediating an ATM- and ataxia telangiectasia-related kinase-dependent growth arrest. To explore further the physiological significance of phosphorylation of p53 on Ser18, we generated mice bearing a serine-to-alanine mutation in p53. Analysis of apoptosis in thymocytes and splenocytes following DNA damage revealed that phosphorylation of serine 18 was required for robust p53-mediated apoptosis. Surprisingly, p53Ser18 phosphorylation did not alter the proliferation rate of embryonic fibroblasts or the p53-mediated G1 arrest induced by DNA damage. In addition, endogenous basal levels and DNA damage-induced levels of p53 were not affected by p53Ser18 phosphorylation. p53Ala18 mice developed normally and were not susceptible to spontaneous tumorigenesis, and the reduced apoptotic function of p53Ala18 did not rescue the embryo-lethal phenotype of Mdm2-null mice. These results indicate that phosphorylation of the ATM target site on p53 specifically regulates p53 apoptotic function and further reveal that phosphorylation of p53 serine 18 is not required for p53-mediated tumor suppression.

scholarly journals C/EBPα Is a DNA Damage-Inducible p53-Regulated Mediator of the G1 Checkpoint in Keratinocytes

2004 ◽  
Vol 24 (24) ◽  
pp. 10650-10660 ◽  
Author(s):  
Kyungsil Yoon ◽  
Robert C. Smart
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Ataxia Telangiectasia ◽  
P53 Protein ◽  
Mouse Skin ◽  
Uvb Radiation ◽  
Ataxia Telangiectasia Mutated ◽  
Basic Leucine Zipper ◽  
Potent Inducer ◽  
Uvb Irradiation

ABSTRACT The basic leucine zipper transcription factor, CCAAT/enhancer binding protein α (C/EBPα), is abundantly expressed in keratinocytes of the skin; however, its function in skin is poorly characterized. UVB radiation is responsible for the majority of human skin cancers. In response to UVB-induced DNA damage, keratinocytes activate cell cycle checkpoints that arrest cell cycle progression and prevent replication of damaged DNA, allowing time for DNA repair. We report here that UVB radiation is a potent inducer of C/EBPα in human and mouse keratinocytes, as well as in mouse skin in vivo. UVB irradiation of keratinocytes resulted in the transcriptional up-regulation of C/EBPα mRNA, producing a >70-fold increase in C/EBPα protein levels. N-Methyl-N′-nitro-N-nitrosoguanidine, etoposide, and bleomycin also induced C/EBPα. UVB-induced C/EBPα was accompanied by an increase in p53 protein and caffeine, an inhibitor of ataxia-telangiectasia-mutated kinase, and ataxia-telangiectasia-mutated and Rad3-related kinase inhibited UVB-induced increases in both C/EBPα and p53. UVB irradiation of p53-null or mutant p53-containing keratinocytes failed to induce C/EBPα. UVB irradiation of C/EBPα knockdown keratinocytes displayed a greatly diminished DNA damage G1 checkpoint, and this was associated with increased sensitivity to UVB-induced apoptosis. Our results uncover a novel role for C/EBPα as a p53-regulated DNA damage-inducible gene that has a critical function in the DNA damage G1 checkpoint response in keratinocytes.

scholarly journals Exploiting replicative stress in gynecological cancers as a therapeutic strategy

2020 ◽  
Vol 30 (8) ◽  
pp. 1224-1238 ◽  
Author(s):  
Natalie YL Ngoi ◽  
Vignesh Sundararajan ◽  
David SP Tan
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Dna Repair ◽  
Ataxia Telangiectasia ◽  
Therapeutic Index ◽  
Cell Cycle Checkpoint ◽  
Mitotic Catastrophe ◽  
Gynecological Cancers ◽  
Replicative Stress ◽  
Cycle Checkpoint

Elevated levels of replicative stress in gynecological cancers arising from uncontrolled oncogenic activation, loss of key tumor suppressors, and frequent defects in the DNA repair machinery are an intrinsic vulnerability for therapeutic exploitation. The presence of replication stress activates the DNA damage response and downstream checkpoint proteins including ataxia telangiectasia and Rad3 related kinase (ATR), checkpoint kinase 1 (CHK1), and WEE1-like protein kinase (WEE1), which trigger cell cycle arrest while protecting and restoring stalled replication forks. Strategies that increase replicative stress while lowering cell cycle checkpoint thresholds may allow unrepaired DNA damage to be inappropriately carried forward in replicating cells, leading to mitotic catastrophe and cell death. Moreover, the identification of fork protection as a key mechanism of resistance to chemo- and poly (ADP-ribose) polymerase inhibitor therapy in ovarian cancer further increases the priority that should be accorded to the development of strategies targeting replicative stress. Small molecule inhibitors designed to target the DNA damage sensors, such as inhibitors of ataxia telangiectasia-mutated (ATM), ATR, CHK1 and WEE1, impair smooth cell cycle modulation and disrupt efficient DNA repair, or a combination of the above, have demonstrated interesting monotherapy and combinatorial activity, including the potential to reverse drug resistance and have entered developmental pipelines. Yet unresolved challenges lie in balancing the toxicity profile of these drugs in order to achieve a suitable therapeutic index while maintaining clinical efficacy, and selective biomarkers are urgently required. Here we describe the premise for targeting of replicative stress in gynecological cancers and discuss the clinical advancement of this strategy.

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

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 507
Author(s):  
Isadora Carolina Betim Pavan ◽  
Andressa Peres de Oliveira ◽  
Pedro Rafael Firmino Dias ◽  
Fernanda Luisa Basei ◽  
Luidy Kazuo Issayama ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Arrest ◽  
Dna Damage Response ◽  
Ataxia Telangiectasia ◽  
General Role ◽  
Cycle Arrest ◽  
Damage Response ◽  
Repair Pathways

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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