S-phase sensing of DNA-protein crosslinks triggers TopBP1-independent ATR activation and p53-mediated cell death by formaldehyde

Wong, Vernon G.; Cash, Haley L; Morse, Jessica L.; Lü, Shan; Zhitkovich, Anatoly

doi:10.4161/cc.20905

Cited by 48 publications

(48 citation statements)

References 69 publications

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“…25,26 In the present work, it was observed that treatment of NB-4 and U937 cells with cordycepin leads to upregulation of p53 expression. As the p53-specific inhibitor PFT-a can partially inhibit cordycepin-induced caspase-3 and caspase-9 activation, we proposed that cordycepin-induced apoptosis in NB-4 and U937 cells is both p53-dependent and -independent.…”

Section: Discussionmentioning

confidence: 74%

Cordycepin induces cell cycle arrest and apoptosis by inducing DNA damage and up-regulation of p53 in Leukemia cells

et al. 2015

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Keywords: apoptosis, cordycepin, cytochrome c, Cdc25A, DNA damage, p53, S-phase arrest Abbreviations: ATM, Ataxia telangiectasia mutated; ATR, ATM and Rad3-related; PI, Propidium iodide; PFT-a, Pifithrin-a; XIAP, X-linked inhibitor of apoptosis protein.Cordycepin, an adenosine analog derived from Cordyceps militaris has been shown to exert anti-tumor activity in many ways. However, the mechanisms by which cordycepin contributes to the anti-tumor still obscure. Here our present work showed that cordycepin inhibits cell growth in NB-4 and U937 cells by inducing apoptosis. Further study showed that cordycepin increases the expression of p53 which promotes the release of cytochrome c from mitochondria to the cytosol. The released cytochrome c can then activate caspase-9 and trigger intrinsic apoptosis. Cordycepin also blocks MAPK pathway by inhibiting the phosphorylation of ERK1/2, and thus sensitizes the apoptosis. In addition, our results showed that cordycepin inhibits the expression of cyclin A2, cyclin E, and CDK2, which leads to the accumulation of cells in S-phase. Moreover, our study showed that cordycepin induces DNA damage and causes degradation of Cdc25A, suggesting that cordycepin-induced S-phase arrest involves activation of Chk2-Cdc25A pathway. In conclusion, cordycepin-induced DNA damage initiates cell cycle arrest and apoptosis which leads to the growth inhibition of NB-4 and U937 cells.

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Section: Discussionmentioning

confidence: 74%

Cordycepin induces cell cycle arrest and apoptosis by inducing DNA damage and up-regulation of p53 in Leukemia cells

et al. 2015

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“…A549 and H460 are human lung epithelial cell lines that we have previously examined for repair of FA-induced DPC and cytotoxic mechanisms (Quievryn and Zhitkovich, 2000; Wong et al, 2012). Both cell lines contain wild-type transcriptional factor p53, which plays a major role in DNA damage-induced cell fate decisions, including those triggered by FA (Wong et al, 2012). Since some regulatory networks are altered in all transformed cell lines, signaling responses to FA were investigated in IMR90 normal human lung fibroblasts.…”

Section: Resultsmentioning

confidence: 99%

“…In addition to their human relevance, low doses help minimize formation and confounding effects of secondary lesions that occur in cells treated with highly toxic concentrations of FA. For example, high FA doses have been found to suppress p53 activation, resulting in a bell-shaped dose response (Wong et al, 2012). The majority of our experiments were conducted with 50–150 μM FA, which covered the physiological range of 30–100 μM FA in human serum of unexposed individuals (IARC, 2006; NTP, 2010) and included a moderately higher dosage of FA occurring locally during inhalation exposures.…”

Section: Resultsmentioning

confidence: 99%

Proteasome activity is important for replication recovery, CHK1 phosphorylation and prevention of G2 arrest after low-dose formaldehyde

Ortega-Atienza

Green

Zhitkovich

2015

Toxicology and Applied Pharmacology

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Formaldehyde (FA) is a human carcinogen with numerous sources of environmental and occupational exposures. This reactive aldehyde is also produced endogenously during metabolism of drugs and other processes. DNA-protein crosslinks (DPC) are considered to be the main genotoxic lesions for FA. Accumulating evidence suggests that DPC repair in high eukaryotes involves proteolysis of crosslinked proteins. Here, we examined a role of the main cellular proteolytic machinery proteasomes in toxic responses of human lung cells to low FA doses. We found that transient inhibition of proteasome activity increased cytotoxicity and diminished clonogenic viability of FA-treated cells. Proteasome inactivation exacerbated suppressive effects of FA on DNA replication and increased the levels of the genotoxic stress marker γ-H2AX in normal human cells. A transient loss of proteasome activity in FA-exposed cells also caused delayed perturbations of cell cycle, which included G2 arrest and a depletion of S-phase populations at FA doses that had no effects in control cells. Proteasome activity diminished p53-Ser15 phosphorylation but was important for FA-induced CHK1 phosphorylation, which is a biochemical marker of DPC proteolysis in replicating cells. Unlike FA, proteasome inhibition had no effect on cell survival and CHK1 phosphorylation by the non-DPC replication stressor hydroxyurea. Overall, we obtained evidence for the importance of proteasomes in protection of human cells against biologically relevant doses of FA. Biochemically, our findings indicate the involvement of proteasomes in proteolytic repair of DPC, which removes replication blockage by these highly bulky lesions.

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“…In addition, it also can decrease the expression of Bcl-2 protein which can maintain mitochondrial homeostasis and prevent mitochondrial release of Cyt C (Ola et al, 2011). The changes of MMP affect the cell signal transduction, cell cycle regulation and DNA replication, while Cell cycle checkpoint controls DNA replication and mitotic starting, in order that it can guarantee the completeness and correctness of chromosomes (Wong et al, 2012). Our results demonstrated that SOD activity in each formaldehyde group was found to be significantly decreased, while MDA content was increased.…”

Section: Discussionmentioning

confidence: 99%

Inhaled Formaldehyde Induces Bone Marrow Toxicity via Oxidative Stress in Exposed Mice

Yu¹,

Song²,

Liu³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Formaldehyde (FA) is an economically important chemical, and has been found to cause various types of toxic damage to the body. Formaldehyde-induced toxic damage involves reactive oxygen species (ROS) that trigger subsequent toxic effects and inflammatory responses, which may increase risk of cancer. Therefore, in the present study, we aimed to investigate the possible toxic mechanism in bone marrow caused by formaldehyde. In accordance with the principle of randomization, the mice were divided into four groups of 6 mice per group. One group was exposed to ambient air and the other three groups were exposed to different concentrations of formaldehyde (20, 40, 80 mg/m 3 ) for 15 days in the respective inhalation chambers, 2h a day. At the end of the 15-day experimental period, all mice were killed. Bone marrow cells were obtained. Some of those were used for the determination of blood cell numbers, bone marrow karyote numbers, CFU-F, superoxide dismutase (SOD) activity and malondialdehyde (MDA) content; others were used for the determination of mitochondrial membrane potential (MMP), cell cycle and Bcl-2, Bax, CytC protein expression. WBC and PLT numbers in median and high dose groups were obvious reduced, but there was no change on RBC numbers. There was also reduced numbers of bone marrow karyotes and CFU-F in the high dose group. SOD activity was decreased, but MDA content was increased. MMP and Bcl-2 expression were decreased with increasing formaldehyde concentration, while expression of Bax and Cyt C was increased. We also observed change in cell cycling, and found that there was S phase arrest in the high dose group. Our study suggested that a certain concentration of formaldehyde could have toxic effects on the hematopoietic system, with oxidative stress as a critical effect.

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S-phase sensing of DNA-protein crosslinks triggers TopBP1-independent ATR activation and p53-mediated cell death by formaldehyde

Cited by 48 publications

References 69 publications

Cordycepin induces cell cycle arrest and apoptosis by inducing DNA damage and up-regulation of p53 in Leukemia cells

Cordycepin induces cell cycle arrest and apoptosis by inducing DNA damage and up-regulation of p53 in Leukemia cells

Proteasome activity is important for replication recovery, CHK1 phosphorylation and prevention of G2 arrest after low-dose formaldehyde

Inhaled Formaldehyde Induces Bone Marrow Toxicity via Oxidative Stress in Exposed Mice

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