Cell Cycle Modulation by Marek’s Disease Virus: The Tegument Protein VP22 Triggers S-Phase Arrest and DNA Damage in Proliferating Cells

Arrest of the cell cycle after DNA damage is believed to promote DNA repair. We aim to investigate the main factors affecting cell cycle arrest of lymphocytes in coke oven workers. A total of 600 workers were included in this study, and their urinary levels of four polycyclic aromatic hydrocarbons (PAH) metabolites, 8-hydroxydeoxyguanosine (8-OHdG), and cell cycle distribution were determined. Urinary PAH metabolites were significantly increased in coke oven workers ( p < 0.01). It was found that only urinary 2-hydroxynaphthalene and 1-hydroxypyrene showed significant positive linear dose–response effects on 8-OHdG in this study population ( ptrend = 0.025 and 0.017, respectively). The dose–response effect was also observed for smoking and drinking on 8-OHdG ( ptrend < 0.001 and 0.034, respectively). Multivariate logistic regression analysis revealed that high levels of urinary 1-hydroxypyrene were associated with a significantly increased risk of S phase arrest (odds ratio (OR) = 1.32, p = 0.03), so as heavy alcohol drinking (OR = 1.31, p = 0.02). Drinking can significantly modify the effects of urinary 1-hydroxypyrene on S phase arrest, during co-exposure to both heavy drinking and median or high 1-hydroxypyrene levels (OR = 3.31, 95% confidence interval (CI) = 1.21–7.63 and OR = 2.56, 95% CI = 1.08–6.06, respectively). Our findings demonstrate that coke oven workers with heavy drinking will cause S phase arrest so as to repair more serious DNA damage.

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Impaired S Phase Arrest in AML Cells with a FLT3-ITD Treated with Clofarabine Allows Prolonged Drug exposure to Reverse the Chemoresistant Phenotype.

Blood ◽

10.1182/blood.v114.22.1000.1000 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1000-1000

Author(s):

Claire Seedhouse ◽

Martin Grundy ◽

Shili Shang ◽

John Ronan ◽

Heather Pimblett ◽

...

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Dna Repair ◽

Cell Cycle Arrest ◽

Short Pulse ◽

S Phase ◽

Mrna Levels ◽

Cycle Arrest ◽

Phase Arrest ◽

S Phase Arrest

Abstract Abstract 1000 Poster Board I-22 We have previously reported that AML cells with a FLT3-ITD have enhanced DNA repair mechanisms following exposure to DNA-damaging drugs which may be a mechanism of chemoresistance. Clofarabine is a novel nucleoside analogue, active in S-phase, with efficacy in AML and is incorporated into DNA as clofarabine triphosphate. Here we show that in FLT3-ITD cells enhanced repair, and therefore resistance to clofarabine-induced DNA damage and toxicity, can be reversed by prolonged drug incubation. When treated with clofarabine, FLT3-ITD-harbouring MOLM13 and MV4.11 cells undergo similar levels of DNA damage (γH2A.X foci) to FLT3 wildtype (WT) cells (HL60 and KG1). After a short pulse of drug the FLT3-ITD cells have a superior repair capability than WT cells; following a 2 hour washout period γH2A.X positivity found immediately after treatment had almost completely disappeared in the FLT3-ITD cells (<10% γH2A.X remaining), whereas in the FLT3-WT cells significant damage (γH2A.X) remained (>40%). Furthermore, after a 1 hour pulse of clofarabine, whereas the FLT3-WT cells under go rapid S phase arrest the S-phase checkpoint fails in the FLT3-ITD cells: reduction in the proportion of cells synthesising DNA is >80% in FLT3-WT cells and <10% in FLT3-ITD cells. Cell cycle arrest in response to DNA damage in S phase is affected via loss of the transcriptional regulator cdc25A. This loss of expression of cdc25A fails to take place in clofarabine-treated FLT3 mutant cells compared to WT cells. In addition, cdc25A mRNA levels are maintained by the FLT3-ITD as demonstrated by siRNA to FLT3 which reduced cdc25A mRNA levels in MV4.11 cells by 87.5%. Primary FLT3 mutant samples from AML patients(n=3) also display impaired cell cycle arrest upon treatment with clofarabine and show enhanced sensitivity on prolonged treatment (24 hours) compared to wildtype samples (n=2). We conclude that there is a reversal of phenotype in mutant FLT3 cells dependant on the length of exposure to clofarabine. Efficient DNA repair renders the cells resistant to a short pulse of the drug, but a failure of cell cycle checkpoint(s) in S phase, mediated by cdc25A, renders the cells sensitive to prolonged exposure. These results may have implications for the scheduling of clofarabine in clinical studies. Disclosures: No relevant conflicts of interest to declare.

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GADD45a Regulates Olaquindox-Induced DNA Damage and S-Phase Arrest in Human Hepatoma G2 Cells via JNK/p38 Pathways

Molecules ◽

10.3390/molecules22010124 ◽

2017 ◽

Vol 22 (1) ◽

pp. 124 ◽

Cited By ~ 12

Author(s):

Daowen Li ◽

Chongshan Dai ◽

Xiayun Yang ◽

Bin Li ◽

Xilong Xiao ◽

...

Keyword(s):

Dna Damage ◽

S Phase ◽

Human Hepatoma ◽

Phase Arrest ◽

S Phase Arrest ◽

G2 Cells

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Induction of S-Phase Arrest in Human Glioma Cells by Selenocysteine, a Natural Selenium-Containing Agent Via Triggering Reactive Oxygen Species-Mediated DNA Damage and Modulating MAPKs and AKT Pathways

Neurochemical Research ◽

10.1007/s11064-016-1854-8 ◽

2016 ◽

Vol 41 (6) ◽

pp. 1439-1447 ◽

Cited By ~ 14

Author(s):

Kun Wang ◽

Xiao-ting Fu ◽

Yuan Li ◽

Ya-jun Hou ◽

Ming-feng Yang ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Dna Damage ◽

Glioma Cells ◽

Reactive Oxygen ◽

S Phase ◽

Oxygen Species ◽

Human Glioma ◽

Human Glioma Cells ◽

Phase Arrest ◽

S Phase Arrest

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Schizosaccharomyces pombe Checkpoint Response to DNA Interstrand Cross-Links

Molecular and Cellular Biology ◽

10.1128/mcb.23.13.4728-4737.2003 ◽

2003 ◽

Vol 23 (13) ◽

pp. 4728-4737 ◽

Cited By ~ 22

Author(s):

Sarah Lambert ◽

Sarah J. Mason ◽

Louise J. Barber ◽

John A. Hartley ◽

Jackie A. Pearce ◽

...

Keyword(s):

Dna Damage ◽

Schizosaccharomyces Pombe ◽

Mammalian Cells ◽

Excision Repair ◽

S Phase ◽

Repair Gene ◽

Phase Arrest ◽

S Phase Arrest ◽

Interstrand Cross Links ◽

Cross Links

ABSTRACT Drugs that produce covalent interstrand cross-links (ICLs) in DNA remain central to the treatment of cancer, but the cell cycle checkpoints activated by ICLs have received little attention. We have used the fission yeast, Schizosaccharomyces pombe, to elucidate the checkpoint responses to the ICL-inducing anticancer drugs nitrogen mustard and mitomycin C. First we confirmed that the repair pathways acting on ICLs in this yeast are similar to those in the main organisms studied to date (Escherichia coli, budding yeast, and mammalian cells), principally nucleotide excision repair and homologous recombination. We also identified and disrupted the S. pombe homologue of the Saccharomyces cerevisiae SNM1/PSO2 ICL repair gene and found that this activity is required for normal resistance to cross-linking agents, but not other forms of DNA damage. Survival and biochemical analysis indicated a key role for the “checkpoint Rad” family acting through the chk1-dependent DNA damage checkpoint in the ICL response. Rhp9-dependent phosphorylation of Chk1 correlates with G2 arrest following ICL induction. In cells able to bypass the G2 block, a second-cycle (S-phase) arrest was observed. Only a transient activation of the Cds1 DNA replication checkpoint factor occurs following ICL formation in wild-type cells, but this is increased and persists in G2 arrest-deficient mutants. This likely reflects the fraction of cells escaping the G2 damage checkpoint and arresting in the subsequent S phase due to ICL replication blocks. Disruption of cds1 confers increased resistance to ICLs, suggesting that this second-cycle S-phase arrest might be a lethal event.

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