The role of dNTP metabolites in control of the embryonic cell cycle

Liu, Boyang; Großhans, Jörg

doi:10.1080/15384101.2019.1665948

Cited by 14 publications

(11 citation statements)

References 115 publications

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“…After mitosis 13, the cell cycle changes to a mode with cytokinesis, a slow S phase, and a G2 phase [5,6]. This change from fast nuclear cycles to slow embryonic cell cycle is linked to the onset of zygotic gene transcription, the degradation of maternal RNAs, consumption of maternal metabolites, and morphological changes [7][8][9][10][11]. The onset of zygotic transcription is necessary and sufficient for remodeling the cell cycle in that the DNA replication checkpoint is activated by an interference of transcription and replication [8,12].…”

Section: Introductionmentioning

confidence: 99%

Fluorescence fluctuation analysis reveals PpV dependent Cdc25 protein dynamics in living embryos

et al. 2020

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The protein phosphatase Cdc25 is a key regulator of the cell cycle by activating Cdk-cyclin complexes. Cdc25 is regulated by its expression levels and post-translational mechanisms. In early Drosophila embryogenesis, Cdc25/Twine drives the fast and synchronous nuclear cycles. A pause in the cell cycle and the remodeling to a more generic cell cycle mode with a gap phase are determined by Twine inactivation and destruction in early interphase 14, in response to zygotic genome activation. Although the pseudokinase Tribbles contributes to the timely degradation of Twine, Twine levels are controlled by additional yet unknown posttranslational mechanisms. Here, we apply a non-invasive method based on fluorescence fluctuation analysis (FFA) to record the absolute concentration profiles of Twine with minute-scale resolution in single living embryos. Employing this assay, we found that Protein phosphatase V (PpV), the homologue of the catalytic subunit of human PP6, ensures appropriately low Twine protein levels at the onset of interphase 14. PpV controls directly or indirectly the phosphorylation of Twine at multiple serine and threonine residues as revealed by phosphosite mapping. Mutational analysis confirmed that these sites are involved in control of Twine protein dynamics, and cell cycle remodeling is delayed in a fraction of the phosphosite mutant embryos. Our data reveal a novel mechanism for control of Twine protein levels and their significance for embryonic cell cycle remodeling.

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Section: Introductionmentioning

confidence: 99%

Fluorescence fluctuation analysis reveals PpV dependent Cdc25 protein dynamics in living embryos

et al. 2020

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“…The turbulent dNTP pools in cells are likely to be related with the dNTP synthesis enzymes, especially the ribonucleotide reductase (RNR), which could catalyze the formation of deoxyribonucleotides from ribonucleotides [ 9 , 25 ]. There are three subunits of mammalian RNR, including RRM1, RRM2, and p53R2, expressed in a cell cycle-dependent manner [ 26 ].…”

Section: Resultsmentioning

confidence: 99%

“…However, some chemotherapeutics could induce the cell cycle blockage, and this process varies according to the cell type, treatment concentration, and duration [ 33 ]. Normally, perturbations in the absolute and relative concentrations of the dNTPs may be related to the inhibition of DNA replication and activation of the S phase checkpoint [ 25 ]. The activated S phase checkpoint arrests cell cycle progression and activates DNA repair, and at worst, leads to apoptosis [ 34 , 35 ].…”

Section: Discussionmentioning

confidence: 99%

Antitumor Mechanism of Hydroxycamptothecin via the Metabolic Perturbation of Ribonucleotide and Deoxyribonucleotide in Human Colorectal Carcinoma Cells

Luo

Zhang

et al. 2021

Molecules

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Hydroxycamptothecin (SN38) is a natural plant extract isolated from Camptotheca acuminate. It has a broad spectrum of anticancer activity through inhibition of DNA topoisomerase I, which could affect DNA synthesis and lead to DNA damage. Thus, the action of SN38 against cancers could inevitably affect endogenous levels of ribonucleotide (RNs) and deoxyribonucleotide (dRNs) that play critical roles in many biological processes, especially in DNA synthesis and repair. However, the exact impact of SN38 on RNs and dRNs is yet to be fully elucidated. In this study, we evaluated the anticancer effect and associated mechanism of SN38 in human colorectal carcinoma HCT 116 cells. As a result, SN38 could decrease the cell viability and induce DNA damage in a concentration-dependent manner. Furthermore, cell cycle arrest and intracellular nucleotide metabolism were perturbed due to DNA damage response, of which ATP, UTP, dATP, and TTP may be the critical metabolites during the whole process. Combined with the expression of deoxyribonucleoside triphosphates synthesis enzymes, our results demonstrated that the alteration and imbalance of deoxyribonucleoside triphosphates caused by SN38 was mainly due to the de novo nucleotide synthesis at 24 h, and subsequently the salvage pathways at 48 h. The unique features of SN38 suggested that it might be recommended as an effective supplementary drug with an anticancer effect.

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“…The remarkably elevated dNTP pools in cells are probably related to the dNTP synthesis enzymes, especially RR that catalyzes the formation of dRNs from RNs (Mathews, 2006;Liu and Grosshans, 2019). Mammalian RR comprises three subunits including RRM1, RRM2, and p53R2, which are expressed in a cell cycle-dependent manner (Yousefi et al, 2014).…”

Section: Remdesivir Upregulated the Riboreductase R2 Expressionmentioning

confidence: 99%

Profiling Ribonucleotide and Deoxyribonucleotide Pools Perturbed by Remdesivir in Human Bronchial Epithelial Cells

Zhang

Luo

et al. 2021

Front. Pharmacol.

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Remdesivir (RDV) has generated much anticipation for its moderate effect in treating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, the unsatisfactory survival rates of hospitalized patients limit its application to the treatment of coronavirus disease 2019 (COVID-19). Therefore, improvement of antiviral efficacy of RDV is urgently needed. As a typical nucleotide analog, the activation of RDV to bioactive triphosphate will affect the biosynthesis of endogenous ribonucleotides (RNs) and deoxyribonucleotides (dRNs), which are essential to RNA and DNA replication in host cells. The imbalance of RN pools will inhibit virus replication as well. In order to investigate the effects of RDV on cellular nucleotide pools and on RNA transcription and DNA replication, cellular RNs and dRNs concentrations were measured by the liquid chromatography-mass spectrometry method, and the synthesis of RNA and DNA was monitored using click chemistry. The results showed that the IC50 values for BEAS-2B cells at exposure durations of 48 and 72 h were 25.3 ± 2.6 and 9.6 ± 0.7 μM, respectively. Ten (10) μM RDV caused BEAS-2B arrest at S-phase and significant suppression of RNA and DNA synthesis after treatment for 24 h. In addition, a general increase in the abundance of nucleotides and an increase of specific nucleotides more than 2 folds were observed. However, the variation of pyrimidine ribonucleotides was relatively slight or even absent, resulting in an obvious imbalance between purine and pyrimidine ribonucleotides. Interestingly, the very marked disequilibrium between cytidine triphosphate (CTP) and cytidine monophosphate might result from the inhibition of CTP synthase. Due to nucleotides which are also precursors for the synthesis of viral nucleic acids, the perturbation of nucleotide pools would block viral RNA replication. Considering the metabolic vulnerability of endogenous nucleotides, exacerbating the imbalance of nucleotide pools imparts great promise to enhance the efficacy of RDV, which possibly has special implications for treatment of COVID-19.

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The role of dNTP metabolites in control of the embryonic cell cycle

Cited by 14 publications

References 115 publications

Fluorescence fluctuation analysis reveals PpV dependent Cdc25 protein dynamics in living embryos

Fluorescence fluctuation analysis reveals PpV dependent Cdc25 protein dynamics in living embryos

Antitumor Mechanism of Hydroxycamptothecin via the Metabolic Perturbation of Ribonucleotide and Deoxyribonucleotide in Human Colorectal Carcinoma Cells

Profiling Ribonucleotide and Deoxyribonucleotide Pools Perturbed by Remdesivir in Human Bronchial Epithelial Cells

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