Diadenosine 5′, 5′′′-P1,P4-tetraphosphate (Ap4A) is synthesized in response to DNA damage and inhibits the initiation of DNA replication

Marriott, Anna; Copeland, Nikki A.; Cunningham, Ryan; Wilkinson, Mark C.; McLennan, Alexander G.; Jones, Nigel J.

doi:10.1016/j.dnarep.2015.06.008

Cited by 18 publications

(37 citation statements)

References 84 publications

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“…When cells are exposed to sublethal DNA damage or repair mutant treatments, Ap 4 A is increased. Ap 4 A inhibits the initiation of DNA replication, but not elongation (23). Ap4A also serves as an alarmone for heat stress in E. coli (24).…”

Section: Discussionmentioning

confidence: 99%

Platelets directly regulate DNA damage and division ofStaphylococcus aureus

Zhang

et al. 2018

FASEB j.

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Platelets (PLTs) are classically used in the clinical setting to maintain hemostasis. Recent evidence supports important roles for PLTs in host inflammatory and immune responses, and PLT-rich plasma has been demonstrated to inhibit the growth of bacteria in vitro and in vivo; however, few studies have examined whether PLTs can inhibit bacterial growth directly, and related mechanisms have not been elucidated further. Accordingly, in this study, we evaluated the effects of PLTs on bacterial growth. We washed and purified PLTs from peripheral blood, then confirmed that PLTs significantly inhibited the growth of Staphylococcus aureus when cocultured in vitro. Moreover, PLTs damaged DNA and blocked cell division in S. aureus. During coculture, PLT-derived TGF-β1 was dramatically down-regulated compared with that in PLT culture alone, and the addition of TGF-β1 to the coculture system promoted the inhibition of PLTs on S. aureus. Analysis of a murine S. aureus infection model demonstrated that the depletion of PLTs exacerbated the severity of infection, whereas the transfusion of PLTs alleviated this infection. Our observations demonstrate that PLTs could directly inhibit the growth of S. aureus by damaging DNA and blockage cell division, and that PLT-derived TGF-β1 may play an important role in this machinery.-Xu, J., Yi, J., Zhang, H., Feng, F., Gu, S., Weng, L., Zhang, J., Chen, Y., An, N., Liu, Z., An, Q., Yin, W., Hu, X. Platelets directly regulate DNA damage and division of Staphylococcus aureus.

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Section: Discussionmentioning

confidence: 99%

Platelets directly regulate DNA damage and division ofStaphylococcus aureus

Zhang

et al. 2018

FASEB j.

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“…The level of intracellular Ap 4 A in log phase KBM-7 and NuKO cells was determined as previously described using a sensitive luminometric assay with slight modifications for use with suspension cells [ 17 , 39 ]. Cells were harvested from suspension by centrifugation at 500 g for 5 min and used for nucleotide extraction.…”

Section: Methodsmentioning

confidence: 99%

“…Ap 4 A was also measured in the growth medium supernatant from these cells, which was filtered through a 0.2 μm Millipore filter, deproteinized with 10% TCA, then assayed as above. ADP-ribosylated derivatives of Ap 4 A (ADPR-Ap 4 A) were separated by ion-exchange chromatography and identified and assayed as previously described [ 17 ].…”

Section: Methodsmentioning

confidence: 99%

“…An increase in Ap 4 A resulting from activation of synthesis, inhibition of degradation or both has been implicated in several intracellular processes. Genotoxic, thermal and other stresses lead to increased Ap 4 A [ 13 – 17 ] and so Ap 4 A has been implicated in the regulation of DNA replication after DNA damage and in promoting apoptosis [ 17 – 19 ]. Ap 4 A may also be raised in response to external ligands and act as an intracellular second messenger [ 20 – 22 ].…”

Section: Introductionmentioning

confidence: 99%

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NUDT2 Disruption Elevates Diadenosine Tetraphosphate (Ap4A) and Down-Regulates Immune Response and Cancer Promotion Genes

et al. 2016

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Regulation of gene expression is one of several roles proposed for the stress-induced nucleotide diadenosine tetraphosphate (Ap4A). We have examined this directly by a comparative RNA-Seq analysis of KBM-7 chronic myelogenous leukemia cells and KBM-7 cells in which the NUDT2 Ap4A hydrolase gene had been disrupted (NuKO cells), causing a 175-fold increase in intracellular Ap4A. 6,288 differentially expressed genes were identified with P < 0.05. Of these, 980 were up-regulated and 705 down-regulated in NuKO cells with a fold-change ≥ 2. Ingenuity® Pathway Analysis (IPA®) was used to assign these genes to known canonical pathways and functional networks. Pathways associated with interferon responses, pattern recognition receptors and inflammation scored highly in the down-regulated set of genes while functions associated with MHC class II antigens were prominent among the up-regulated genes, which otherwise showed little organization into major functional gene sets. Tryptophan catabolism was also strongly down-regulated as were numerous genes known to be involved in tumor promotion in other systems, with roles in the epithelial-mesenchymal transition, proliferation, invasion and metastasis. Conversely, some pro-apoptotic genes were up-regulated. Major upstream factors predicted by IPA® for gene down-regulation included NFκB, STAT1/2, IRF3/4 and SP1 but no major factors controlling gene up-regulation were identified. Potential mechanisms for gene regulation mediated by Ap4A and/or NUDT2 disruption include binding of Ap4A to the HINT1 co-repressor, autocrine activation of purinoceptors by Ap4A, chromatin remodeling, effects of NUDT2 loss on transcript stability, and inhibition of ATP-dependent regulatory factors such as protein kinases by Ap4A. Existing evidence favors the last of these as the most probable mechanism. Regardless, our results suggest that the NUDT2 protein could be a novel cancer chemotherapeutic target, with its inhibition potentially exerting strong anti-tumor effects via multiple pathways involving metastasis, invasion, immunosuppression and apoptosis.

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“…There is also evidence that Ap 4 A inhibits the initiation of DNA replication. It is also proposed that Ap 4 A acts as an important inducible ligand in the DNA damage response to prevent the replication of damaged DNA [184]. In contrast, the increase in the ratio of Ap 3 A/Ap 4 A in human HL60 cells can induce apoptosis [164].…”

Section: Function Of Uncommon Nucleotidesmentioning

confidence: 99%

New Insight into Plant Signaling: Extracellular ATP and Uncommon Nucleotides

Pietrowska‐Borek

Dobrogojski

Sobieszczuk‐Nowicka

et al. 2020

Cells

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New players in plant signaling are described in detail in this review: extracellular ATP (eATP) and uncommon nucleotides such as dinucleoside polyphosphates (NpnN’s), adenosine 5′-phosphoramidate (NH2-pA), and extracellular NAD+ and NADP+ (eNAD(P)+). Recent molecular, physiological, and biochemical evidence implicating concurrently the signaling role of eATP, NpnN’s, and NH2-pA in plant biology and the mechanistic events in which they are involved are discussed. Numerous studies have shown that they are often universal signaling messengers, which trigger a signaling cascade in similar reactions and processes among different kingdoms. We also present here, not described elsewhere, a working model of the NpnN’ and NH2-pA signaling network in a plant cell where these nucleotides trigger induction of the phenylpropanoid and the isochorismic acid pathways yielding metabolites protecting the plant against various types of stresses. Through these signals, the plant responds to environmental stimuli by intensifying the production of various compounds, such as anthocyanins, lignin, stilbenes, and salicylic acid. Still, more research needs to be performed to identify signaling networks that involve uncommon nucleotides, followed by omic experiments to define network elements and processes that are controlled by these signals.

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Diadenosine 5′, 5′′′-P1,P4-tetraphosphate (Ap4A) is synthesized in response to DNA damage and inhibits the initiation of DNA replication

Cited by 18 publications

References 84 publications

Platelets directly regulate DNA damage and division ofStaphylococcus aureus

Platelets directly regulate DNA damage and division ofStaphylococcus aureus

NUDT2 Disruption Elevates Diadenosine Tetraphosphate (Ap4A) and Down-Regulates Immune Response and Cancer Promotion Genes

New Insight into Plant Signaling: Extracellular ATP and Uncommon Nucleotides

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