scholarly journals NAD consumption by PARP1 in response to DNA damage triggers metabolic shift critical for damaged cell survival

2018 ◽  
Author(s):  
Michael M. Murata ◽  
Xiangduo Kong ◽  
Emmanuel Moncada ◽  
Yumay Chen ◽  
Ping Wang ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Survival ◽  
Cell Fate ◽  
Nuclear Dna ◽  
Critical Role ◽  
Fluorescence Lifetime Imaging ◽  
Dependent Manner ◽  
Spatiotemporal Resolution ◽  
Parp Activation ◽  
Laser Microirradiation

AbstractDNA damage signaling is critical for the maintenance of genome integrity and cell fate decision. Poly(ADP-ribose) polymerase 1 (PARP1) is a DNA damage sensor rapidly activated in a damage dose and complexity-dependent manner playing a critical role in the initial chromatin organization and DNA repair pathway choice at damage sites. However, the cell-wide consequence of its activation in damaged cells is not well delineated. Using the phasor approach to fluorescence lifetime imaging microscopy (FLIM) and fluorescence-based biosensors in combination with laser microirradiation, we found a rapid cell-wide increase of the bound/free NADH ratio in response to nuclear DNA damage, which is triggered by NAD+ depletion by PARP activation. This change is linked to the metabolic balance shift to oxidative phosphorylation (oxphos) over glycolysis. Inhibition of the respiratory chain resulted in rapid PARP-dependent ATP reduction and intracellular acidification, and eventually, PARP-dependent, AIF-independent, apoptosis indicating that oxphos becomes critical for damaged cell survival. The results reveal the novel pro-survival effect of PARP activation through a change in cellular metabolism, and demonstrate how unique applications of advanced fluorescence imaging technologies in combination with laser microirradiation can be a powerful tool to interrogate damage-induced metabolic changes at high spatiotemporal resolution in a live cell.

scholarly journals NAD+ consumption by PARP1 in response to DNA damage triggers metabolic shift critical for damaged cell survival

2019 ◽  
Vol 30 (20) ◽  
pp. 2584-2597 ◽  
Author(s):  
Michael M. Murata ◽  
Xiangduo Kong ◽  
Emmanuel Moncada ◽  
Yumay Chen ◽  
Hiromi Imamura ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Survival ◽  
Cell Fate ◽  
Nuclear Dna ◽  
Critical Role ◽  
Fluorescence Lifetime Imaging ◽  
Dependent Manner ◽  
Spatiotemporal Resolution ◽  
Parp Activation ◽  
Laser Microirradiation

DNA damage signaling is critical for the maintenance of genome integrity and cell fate decision. Poly(ADP-ribose) polymerase 1 (PARP1) is a DNA damage sensor rapidly activated in a damage dose- and complexity-dependent manner playing a critical role in the initial chromatin organization and DNA repair pathway choice at damage sites. However, our understanding of a cell-wide consequence of its activation in damaged cells is still limited. Using the phasor approach to fluorescence lifetime imaging microscopy and fluorescence-based biosensors in combination with laser microirradiation, we found a rapid cell-wide increase of the bound NADH fraction in response to nuclear DNA damage, which is triggered by PARP-dependent NAD+ depletion. This change is linked to the metabolic balance shift to oxidative phosphorylation (oxphos) over glycolysis. Inhibition of oxphos, but not glycolysis, resulted in parthanatos due to rapid PARP-dependent ATP deprivation, indicating that oxphos becomes critical for damaged cell survival. The results reveal the novel prosurvival response to PARP activation through a change in cellular metabolism and demonstrate how unique applications of advanced fluorescence imaging and laser microirradiation-induced DNA damage can be a powerful tool to interrogate damage-induced metabolic changes at high spatiotemporal resolution in a live cell.

scholarly journals Crosstalk of the Caspase Family and Mammalian Target of Rapamycin Signaling

2021 ◽  
Vol 22 (2) ◽  
pp. 817
Author(s):  
Junfang Yan ◽  
Yi Xie ◽  
Jing Si ◽  
Lu Gan ◽  
Hongyan Li ◽  
...  
Keyword(s):  
Cell Growth ◽  
Cell Survival ◽  
Cell Fate ◽  
Cellular Stress ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Signaling ◽  
Target Of Rapamycin ◽  
Dependent Manner ◽  
Caspase Family ◽  
Mediate Cell

Cell can integrate the caspase family and mammalian target of rapamycin (mTOR) signaling in response to cellular stress triggered by environment. It is necessary here to elucidate the direct response and interaction mechanism between the two signaling pathways in regulating cell survival and determining cell fate under cellular stress. Members of the caspase family are crucial regulators of inflammation, endoplasmic reticulum stress response and apoptosis. mTOR signaling is known to mediate cell growth, nutrition and metabolism. For instance, over-nutrition can cause the hyperactivation of mTOR signaling, which is associated with diabetes. Nutrition deprivation can inhibit mTOR signaling via SH3 domain-binding protein 4. It is striking that Ras GTPase-activating protein 1 is found to mediate cell survival in a caspase-dependent manner against increasing cellular stress, which describes a new model of apoptosis. The components of mTOR signaling-raptor can be cleaved by caspases to control cell growth. In addition, mTOR is identified to coordinate the defense process of the immune system by suppressing the vitality of caspase-1 or regulating other interferon regulatory factors. The present review discusses the roles of the caspase family or mTOR pathway against cellular stress and generalizes their interplay mechanism in cell fate determination.

scholarly journals ATM regulates a DNA damage response posttranscriptional RNA operon in lymphocytes

Blood ◽  
2011 ◽  
Vol 117 (8) ◽  
pp. 2441-2450 ◽  
Author(s):  
Krystyna Mazan-Mamczarz ◽  
Patrick R. Hagner ◽  
Yongqing Zhang ◽  
Bojie Dai ◽  
Elin Lehrmann ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Ataxia Telangiectasia ◽  
Rna Binding ◽  
Critical Role ◽  
Cell Cycle Checkpoints ◽  
Dependent Manner ◽  
Damage Response ◽  
Multiple Cell

Abstract Maintenance of genomic stability depends on the DNA damage response, a biologic barrier in early stages of cancer development. Failure of this response results in genomic instability and high predisposition toward lymphoma, as seen in patients with ataxia-telangiectasia mutated (ATM) dysfunction. ATM activates multiple cell-cycle checkpoints and DNA repair after DNA damage, but its influence on posttranscriptional gene expression has not been examined on a global level. We show that ionizing radiation modulates the dynamic association of the RNA-binding protein HuR with target mRNAs in an ATM-dependent manner, potentially coordinating the genotoxic response as an RNA operon. Pharmacologic ATM inhibition and use of ATM-null cells revealed a critical role for ATM in this process. Numerous mRNAs encoding cancer-related proteins were differentially associated with HuR depending on the functional state of ATM, in turn affecting expression of encoded proteins. The findings presented here reveal a previously unidentified role of ATM in controlling gene expression posttranscriptionally. Dysregulation of this DNA damage response RNA operon is probably relevant to lymphoma development in ataxia-telangiectasia persons. These novel RNA regulatory modules and genetic networks provide critical insight into the function of ATM in oncogenesis.

scholarly journals YBX1 is required for maintaining myeloid leukemia cell survival by regulating BCL2 stability in an m6A-dependent manner

Blood ◽  
2021 ◽  
Author(s):  
Mengdie Feng ◽  
Xueqin Xie ◽  
Guoqiang Han ◽  
Tiantian Zhang ◽  
Yashu Li ◽  
...  
Keyword(s):  
Cell Survival ◽  
Myeloid Leukemia ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Critical Role ◽  
Leukemia Cell ◽  
Dependent Manner ◽  
Myeloid Leukemia Cell

RNA-binding proteins (RBPs) are critical regulators of transcription and translation that are often dysregulated in cancer. Although RBPs are increasingly appreciated as being important for normal hematopoiesis and for hematological malignancies as oncogenes or tumor suppressors, essential RBPs for leukemia maintenance and survival remain elusive. Here we show that YBX1 is specifically required for maintaining myeloid leukemia cell survival in an m6A-dependent manner. We found that expression of YBX1 is significantly upregulated in myeloid leukemia cells, and deletion of YBX1 dramatically induces apoptosis, promotes differentiation, coupled with reduced proliferation and impaired leukemic capacity of primary human and mouse acute myeloid leukemia (AML) cells in vitro and in vivo. Loss of YBX1 does not obviously affect normal hematopoiesis. Mechanistically, YBX1 interacts with IGF2BPs and stabilizes m6A-tagged RNA. Moreover, YBX1 deficiency dysregulates the expression of apoptosis-related genes, and promotes mRNA decay of MYC and BCL2 in an m6A-dependent manner, which contributes to the defective survival due to YBX1 deletion. Thus, our findings uncover a selective and critical role of YBX1 in maintaining myeloid leukemia survival that might provide a rationale for the therapeutic targeting of YBX1 in myeloid leukemia.

scholarly journals SRC activation skews cell fate from apoptosis to senescence

2021 ◽  
Author(s):  
Carlos Anerillas ◽  
Allison Herman ◽  
Martina Rossi ◽  
Rachel Munk ◽  
Elin Lehrmann ◽  
...  
Keyword(s):  
Dna Damage ◽  
Health Outcomes ◽  
Cell Survival ◽  
Cell Fate ◽  
Cell Apoptosis ◽  
Senescent Cell ◽  
Tissue Accumulation ◽  
Complex Adaptive ◽  
Pharmacologic Inhibition ◽  
Improve Health

Abstract Cells responding to DNA damage implement complex adaptive programs that often culminate in two distinct outcomes: apoptosis or senescence. To systematically identify factors driving each response, we analyzed human IMR-90 fibroblasts exposed to increasing doses of the genotoxin etoposide and identified SRC as a key kinase contributing to this dichotomous decision. SRC was activated by low (50 μM) etoposide but not by high (200 μM) etoposide levels. With low DNA damage, SRC-mediated activation of p38 critically promoted cell survival and senescence, and increased pro-survival BCL2L2 levels, while SRC-mediated repression of p53 prevented a rise in pro-apoptotic PUMA levels. With high DNA damage, SRC was not activated, leading to elevation of p53, inhibition of p38, and apoptosis. In mice exposed to DNA damage, pharmacologic inhibition of SRC prevented tissue accumulation of senescent cells. We propose that inhibiting SRC could be exploited to induce senescent-cell apoptosis in tissues to improve health outcomes.

scholarly journals Polarization and cell-fate decision facilitated by the adaptor Ste50 in Saccharomyces cerevisiae

2021 ◽  
Author(s):  
Nusrat Sharmeen ◽  
Chris Law ◽  
Cunle Wu
Keyword(s):  
Cell Fate ◽  
Critical Role ◽  
Time Lapse ◽  
Yeast Cells ◽  
Cell Cortex ◽  
Dependent Manner ◽  
Pheromone Response ◽  
Concentration Dependent Manner ◽  
Directional Growth ◽  
Fate Decision

Polarization or directional growth is a major morphological change that occurs in yeast cells during pheromone response to mate with the opposite partner. In the pheromone signaling pathway, the adaptor Ste50 is required to bind MAP3K Ste11 for proper polarization; cells lacking Ste50 are impaired in polarization. Direct involvement of Ste50 in the polarization process has not been explored systematically. Here, we used single-cell fluorescent time-lapse microscopy to characterize Ste50 involvement in the establishment of cell polarity. We found early localization of Ste50 patches on the cell cortex that mark the point of shmoo initiation, these polarity sites move, and patches remain associated with the growing shmoo tip in a pheromone concentration-dependent manner until shmoo maturation. By quantitative analysis we show that polarization corelates with the rising levels of Ste50 enabling rapid individual cell responses to pheromone that corresponds to a critical level of Ste50 at the initial G1 phase. Suggesting Ste50 to be a pheromone responsive gene. We exploited the quantitative differences in the pattern of Ste50 expression to corelate with the cell-cell phenotypic heterogeneity showing Ste50 involvement in the cellular differentiation choices. Taken together, these findings present spatiotemporal localization of Ste50 during yeast polarization, suggesting that Ste50 is a component of the polarisome, and plays a critical role in regulating the polarized growth of shmoo during pheromone response.

scholarly journals DNA Damage- But Not Enzalutamide-Induced Senescence in Prostate Cancer Promotes Senolytic Bcl-xL Inhibitor Sensitivity

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1593 ◽  
Author(s):  
Nicolas Malaquin ◽  
Arthur Vancayseele ◽  
Sophie Gilbert ◽  
Laureen Antenor-Habazac ◽  
Marc-Alexandre Olivier ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Damage ◽  
Cell Death ◽  
Cell Fate ◽  
Cancer Cell ◽  
Parp Inhibitors ◽  
Model Systems ◽  
Dependent Manner ◽  
Systematic Analysis ◽  
Context Dependent

Cellular senescence is a natural tumor suppression mechanism defined by a stable proliferation arrest. In the context of cancer treatment, cancer cell therapy-induced senescence (TIS) is emerging as an omnipresent cell fate decision that can be pharmacologically targeted at the molecular level to enhance the beneficial aspects of senescence. In prostate cancer (PCa), TIS has been reported using multiple different model systems, and a more systematic analysis would be useful to identify relevant senescence manipulation molecular targets. Here we show that a spectrum of PCa senescence phenotypes can be induced by clinically relevant therapies. We found that DNA damage inducers like irradiation and poly (ADP-ribose) polymerase1 (PARP) inhibitors triggered a stable PCa-TIS independent of the p53 status. On the other hand, enzalutamide triggered a reversible senescence-like state that lacked evidence of cell death or DNA damage. Using a small senolytic drug panel, we found that senescence inducers dictated senolytic sensitivity. While Bcl-2 family anti-apoptotic inhibitor were lethal for PCa-TIS cells harboring evidence of DNA damage, they were ineffective against enzalutamide-TIS cells. Interestingly, piperlongumine, which was described as a senolytic, acted as a senomorphic to enhance enzalutamide-TIS proliferation arrest without promoting cell death. Overall, our results suggest that TIS phenotypic hallmarks need to be evaluated in a context-dependent manner because they can vary with senescence inducers, even within identical cancer cell populations. Defining this context-dependent spectrum of senescence phenotypes is key to determining subsequent molecular strategies that target senescent cancer cells.

scholarly journals DNA-Damage-Induced Alternative Splicing of p53

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 251
Author(s):  
Jing Chen ◽  
Dadong Zhang ◽  
Xiaodi Qin ◽  
Kouros Owzar ◽  
Jennifer J. McCann ◽  
...  
Keyword(s):  
Dna Damage ◽  
Alternative Splicing ◽  
Cell Fate ◽  
Stress Responses ◽  
Translational Regulation ◽  
P53 Protein ◽  
Functional Divergence ◽  
Critical Role ◽  
Protein Interactome ◽  
Wide Range

Cellular responses to DNA damage and other stresses are important determinants of mutagenesis and impact the development of a wide range of human diseases. TP53 is highly mutated in human cancers and plays an essential role in stress responses and cell fate determination. A central dogma of p53 induction after DNA damage has been that the induction results from a transient increase in the half-life of the p53 protein. Our laboratory recently demonstrated that this long-standing paradigm is an incomplete picture of p53 regulation by uncovering a critical role for protein translational regulation in p53 induction after DNA damage. These investigations led to the discovery of a DNA-damage-induced alternative splicing (AS) pathway that affects p53 and other gene products. The damage-induced AS of p53 pre-mRNA generates the beta isoform of p53 (p53β) RNA and protein, which is specifically required for the induction of cellular senescence markers after ionizing irradiation (IR). In an attempt to elucidate the mechanisms behind the differential regulation and apparent functional divergence between full-length (FL) p53 and the p53β isoform (apoptosis versus senescence, respectively), we identified the differential transcriptome and protein interactome between these two proteins that may result from the unique 10-amino-acid tail in p53β protein.

scholarly journals p53 drives premature neuronal differentiation in response to radiation-induced DNA damage during early neurogenesis

2020 ◽  
Author(s):  
André-Claude Mbouombouo Mfossa ◽  
Mieke Verslegers ◽  
Tine Verreet ◽  
Haris bin Fida ◽  
Mohamed Mysara ◽  
...  
Keyword(s):  
Dna Damage ◽  
Neuronal Differentiation ◽  
Cell Fate ◽  
Epithelial To Mesenchymal Transition ◽  
Brain Size ◽  
Critical Role ◽  
Neural Progenitor Cell ◽  
Developmental Defects ◽  
Mesenchymal Transition ◽  
Radiation Induced

Abstractp53 regulates the cellular DNA damage response (DDR). Hyperactivation of p53 during embryonic development, however, can lead to a range of developmental defects including microcephaly. Here, we induce microcephaly by acute irradiation of mouse fetuses at the onset of neurogenesis. Besides a classical DDR culminating in massive apoptosis, we observe ectopic neurons in the subventricular zone in the brains of irradiated mice, indicative of premature neuronal differentiation. A transcriptomic study indicates that p53 activates both DDR genes and differentiation-associated genes. In line with this, mice with a targeted inactivation of Trp53 in the dorsal forebrain, do not show this ectopic phenotype and partially restore brain size after irradiation. Irradiation furthermore induces an epithelial-to-mesenchymal transition-like process resembling the radiation-induced proneural-mesenchymal transition in glioma and glioma stem-like cells. Our results demonstrate a critical role for p53 beyond the DDR as a regulator of neural progenitor cell fate in response to DNA damage.

scholarly journals Saturated FFAs, Palmitic Acid and Stearic Acid, Induce Apoptosis in Human Granulosa Cells

Endocrinology ◽  
2001 ◽  
Vol 142 (8) ◽  
pp. 3590-3597 ◽  
Author(s):  
Yi-Ming Mu ◽  
Toshihiko Yanase ◽  
Yoshihiro Nishi ◽  
Atsushi Tanaka ◽  
Masayuki Saito ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Arachidonic Acid ◽  
Stearic Acid ◽  
Palmitic Acid ◽  
Cell Survival ◽  
Granulosa Cell ◽  
Granulosa Cells ◽  
Critical Role ◽  
Dependent Manner ◽  
Human Granulosa Cells

Abstract Obesity is associated with insulin resistance and some reproductive abnormalities. Circulating FFAs are often elevated in obese subjects and are also closely linked to insulin resistance. In this study, we demonstrated that saturated FFAs, such as palmitic acid and stearic acid, markedly suppressed the granulosa cell survival in a time- and dose-dependent manner. Polyunsaturated FFA, arachidonic acid, had no effect on the cell survival, even at supraphysiological concentrations. The suppressive effect of saturated FFAs on cell survival was caused by apoptosis, as evidenced by DNA ladder formation and annexin V-EGFP/propidium iodide staining of the cells. The apoptotic effects of palmitic acid and stearic acid were unrelated to the increase of ceramide generation or nitric oxide production and were also completely blocked by Triacsin C, an inhibitor of acylcoenzyme A synthetase. In addition, acylcoenzyme A, pamitoylcoenzyme A, and stearylcoenzyme A markedly suppressed granulosa cell survival, whereas arachidonoylcoenzyme A had no such effect, and this finding was consistent with the effect of the respective FFA form. Surprisingly, arachidonic acid instead showed a protective effect on palmitic acid- and stearic acid-induced cell apoptosis. A Western blot analysis showed the apoptosis of the granulosa cells induced by palmitic acid to be accompanied by the down-regulation of an apoptosis inhibitor, Bcl-2, and the up-regulation of an apoptosis effector, Bax. These results indicate that saturated FFAs induce apoptosis in human granulosa cells caused by the metabolism of the respective acylcoenzyme A form, and the actual composition of circulating FFAs may thus play a critical role in the apoptotic events of human granulosa cells. These effects of FFAs on granulosa cell survival may be a possible mechanism for reproductive abnormalities, such as amenorrhea, which is frequently observed in obese women.

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