scholarly journals Genome-wide screen of cell-cycle regulators in normal and tumor cells identifies a differential response to nucleosome depletion

2016 ◽  
Author(s):  
Maria Sokolova ◽  
Mikko Turunen ◽  
Oliver Mortusewicz ◽  
Teemu Kivioja ◽  
Patrick Herr ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cancer Cells ◽  
Tumor Cells ◽  
S Phase ◽  
Replication Forks ◽  
Cell Cycle Regulators ◽  
Normal Cells ◽  
Viable Cells ◽  
Genome Wide

AbstractTo identify cell cycle regulators that enable cancer cells to replicate DNA and divide in an unrestricted manner, we performed a parallel genome-wide RNAi screen in normal and cancer cell lines. In addition to many shared regulators, we found that tumor and normal cells are differentially sensitive to loss of the histone genes transcriptional regulator CASP8AP2. In cancer cells, loss of CASP8AP2 leads to a failure to synthesize sufficient amount of histones in the S-phase of the cell cycle, resulting in slowing of individual replication forks. Despite this, DNA replication fails to arrest, and tumor cells progress in an elongated S-phase that lasts several days, finally resulting in death of most of the affected cells. In contrast, depletion of CASP8AP2 in normal cells triggers a response that arrests viable cells in S-phase. The arrest is dependent on p53, and preceded by accumulation of markers of DNA damage, indicating that nucleosome depletion is sensed in normal cells via a DNA-damage-like response that is defective in tumor cells.

scholarly journals Inhibition of DNA Repair in Cancer Therapy: Toward a Multi-Target Approach

2020 ◽  
Vol 21 (18) ◽  
pp. 6684
Author(s):  
Samuele Lodovichi ◽  
Tiziana Cervelli ◽  
Achille Pellicioli ◽  
Alvaro Galli
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Dna Repair ◽  
Cancer Therapy ◽  
Clinical Outcome ◽  
Cancer Cells ◽  
Cell Cycle Checkpoint ◽  
Normal Cells ◽  
Cycle Checkpoint ◽  
Repair Pathways

Alterations in DNA repair pathways are one of the main drivers of cancer insurgence. Nevertheless, cancer cells are more susceptible to DNA damage than normal cells and they rely on specific functional repair pathways to survive. Thanks to advances in genome sequencing, we now have a better idea of which genes are mutated in specific cancers and this prompted the development of inhibitors targeting DNA repair players involved in pathways essential for cancer cells survival. Currently, the pivotal concept is that combining the inhibition of mechanisms on which cancer cells viability depends is the most promising way to treat tumorigenesis. Numerous inhibitors have been developed and for many of them, efficacy has been demonstrated either alone or in combination with chemo or radiotherapy. In this review, we will analyze the principal pathways involved in cell cycle checkpoint and DNA repair focusing on how their alterations could predispose to cancer, then we will explore the inhibitors developed or in development specifically targeting different proteins involved in each pathway, underscoring the rationale behind their usage and how their combination and/or exploitation as adjuvants to classic therapies could help in patients clinical outcome.

scholarly journals Caspase-2 regulates S-phase cell cycle events to protect from DNA damage accumulation independent of apoptosis

2021 ◽  
Author(s):  
Ashley Boice ◽  
Raj Kumari Pandita ◽  
Karla Lopez ◽  
Melissa J Pourpak ◽  
Chloe I Charendoff ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Division ◽  
S Phase ◽  
Phase Cell ◽  
Replication Forks ◽  
Cycle Arrest ◽  
Dividing Cells ◽  
Caspase 2 ◽  
Stalled Replication Forks

In addition to its classical role in apoptosis, accumulating evidence suggests that caspase-2 has non-apoptotic functions, including regulation of cell division. Loss of caspase-2 is known to increase proliferation rates but how caspase-2 is regulating this process is currently unclear. We show that caspase-2 is activated in dividing cells in G1- and early S-phase. In the absence of caspase-2, cells exhibit numerous S-phase defects including delayed exit from S-phase, S-phase-associated chromosomal aberrations, and increased DNA damage following S-phase arrest. In addition, caspase-2-deficient cells have a higher frequency of stalled replication forks, decreased DNA fiber length, and impeded progression of DNA replication tracts. This indicates that caspase-2 reduces replication stress and promotes replication fork protection to maintain genomic stability. These functions are independent of the pro-apoptotic function of caspase-2 because blocking caspase-2-induced cell death had no effect on cell division or DNA damage-induced cell cycle arrest. Thus, our data supports a model where caspase-2 regulates cell cycle events to protect from the accumulation of DNA damage independently of its pro-apoptotic function.

Krebszellkinetik und Krebs-Mehrschritt-Therapie / Cancer Cell Kinetics and Cancer Multistep Therapy

1972 ◽  
Vol 27 (12) ◽  
pp. 1547-1566 ◽  
Author(s):  
Manfred Von Ardenne
Keyword(s):  
Cell Cycle ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Cancer Cell ◽  
Glucose Concentration ◽  
Time Span ◽  
Normal Cells ◽  
Tumor Tissues ◽  
Wide Range ◽  
Sensitive Phase

Basic to the proposed therapeutic usage of the difference in the in-vivo proliferation control between cancer and normal cells are the temporary selective increase in the proliferation rate and number of cancer cells in all kinds of tumors but without increase of the proliferative activity of normal cells. To further this aim, measurements of cellular kinetics are used, in connection with the glycolysis of different tumor tissues under saturation conditions, with the relationship between cancer cell cycle and glycolytic rate, or the local glucose level respectively, with the wide range of glucose concentrations in tumor regions which differ the conditions of supply, with the pO2-value critical for tumor growth (≈ 0.4 Torr), with the pO2-distribution in tumor tissues and the time distribution of cell cycles in human and animal cancerous tissues. From an approximative description of the cytostatic effects in different tumor regions and its validity limits it is estimated that the sensitivity towarts therapy is decreased to as low as one-tenth in poorly supplied tumor regions. These particular fractions of the tumor tissues determine the degree of tumor resistence. Additionally, from these considerations steps can be derived which could be important for multiplying the effect of the cytostatic attack on the critical tumor regions with poor supply conditions. These steps include: a) usage of combinations of cytostatic agents directed against all three sensitive phases of the cell cycle (S-G2-M); b) increase in blood glucose concentration to about 300 mg% for an optimum time span prior to the initiation of the main therapeutic process; c) increase in pO2 of the inspiration air to 320 or 400 Torr and in the degree of pO2 utilization by the use of specific pharmaceutic agents for the chosen time span preceding the main therapy; d) stimulation of tumor vascularization preceding the main therapy; e) decrease in the fraction of tumor cells utilizing glucose and O2 as a consequence of a post-therapy treatment 72 hours after the main therapy. The increase in the fraction of cells in a sensitive phase of the cell cycle is reached folowing synchronization after increasing the glucose concentration until saturation of the glycolytic capacity. Reasons are given, why the cytostatic attack has to be supplemented by other selective mechanisms which damage the tumor cell independent of the phase of the cell cycle. Such a mechanism is the lysosomal cytolytic chain reaction. Here, the death of tumor cells occurring during a sensitive phase of the cell cycle as a consequence of the cytostatic attack helps to damage cancer cells which are in the insensitive phase. A further mechanism of this kind is the immunological attack, which is also a component of multi-step cancer therapy

scholarly journals Polo-Like Kinase 1 Depletion Induces DNA Damage in Early S Prior to Caspase Activation

2009 ◽  
Vol 29 (10) ◽  
pp. 2609-2621 ◽  
Author(s):  
Hyungshin Yim ◽  
Raymond L. Erikson
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Dna Synthesis ◽  
Cancer Cells ◽  
S Phase ◽  
Mitotic Catastrophe ◽  
Serum Starvation ◽  
Dna Integrity ◽  
Normal Cells ◽  
Sequence Of Events

ABSTRACT Polo-like kinase 1 (Plk1) plays several roles in mitosis, and it has been suggested to have a role in tumorigenesis. We have previously reported that Plk1 depletion results in cell death in cancer cells, whereas normal cells survive similar depletion. However, Plk1 depletion together with p53 depletion induces cell death in normal cells as well. This communication presents evidence on the sequence of events that leads to cell death in cancer cells. DNA damage is detected at the first S phase following Plk1 depletion and is more severe in Plk1-depleted p53-null cancer cells. As a consequence of Plk1 depletion using lentivirus-based small interfering RNA techniques, prereplicative complex (pre-RC) formation is disrupted at the G1/S transition, and DNA synthesis is reduced during S phase of the first cycle after depletion. The levels of geminin, an inhibitor of DNA pre-RC, and Emi1, an inhibitor of anaphase-promoting complex/cyclosome, are elevated in Plk1-depleted cells. The rate of cell cycling is slower in Plk1-depleted cells than in control cells when synchronized by serum starvation. Plk1 depletion results in disrupted DNA pre-RC formation, reduced DNA synthesis, and DNA damage before cells display severe mitotic catastrophe or apoptosis. Our data suggest that Plk1 is required for cell cycle progression not only in mitosis but also for DNA synthesis, maintenance of DNA integrity, and prevention of cell death.

scholarly journals DNA Damage Enhanced by the Attenuation of SLD5 Delays Cell Cycle Restoration in Normal Cells but Not in Cancer Cells

PLoS ONE ◽  
2014 ◽  
Vol 9 (10) ◽  
pp. e110483 ◽  
Author(s):  
Zhi-Yuan Gong ◽  
Hiroyasu Kidoya ◽  
Tomomi Mohri ◽  
Yinglu Han ◽  
Nobuyuki Takakura
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cancer Cells ◽  
Normal Cells

scholarly journals Computational Model of G2-M DNA Damage Checkpoint Regulation in Normal and p53-null Cancer Cells

2020 ◽  
Author(s):  
Yongwoon Jung ◽  
Pavel Kraikivski
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Computational Model ◽  
Cell Cycle Arrest ◽  
Cancer Cells ◽  
Cell Cycle Progression ◽  
Dna Damage Checkpoint ◽  
Cycle Progression ◽  
Normal Cells ◽  
Cycle Arrest

AbstractCancer and normal cells can respond differently to the same stressful conditions. Their dynamic responses under normal and stressful conditions are governed by complex molecular regulatory networks. We developed a computational model of G2-M DNA damage checkpoint regulation to study normal and cancer cell cycle progression under normal and stressful conditions. Our model is successful in explaining cancer cell cycle arrest in conditions when some cell cycle and DNA damage checkpoint regulators are inhibited, whereas the same conditions only delay entry into mitosis in normal cells. We use the model to explain known phenotypes of gene deletion mutants and predict phenotypes of yet uncharacterized mutants in normal and cancer cells. We also use sensitive analyses to identify the ranges of model parameter values that lead to the cell cycle arrest in cancer cells. Our results can be used to predict the effect of a potential treatment on cell cycle progression of normal and cancer cells.

scholarly journals Genome-wide screen of cell-cycle regulators in normal and tumor cells identifies a differential response to nucleosome depletion

Cell Cycle ◽  
2017 ◽  
Vol 16 (2) ◽  
pp. 189-199 ◽  
Author(s):  
Maria Sokolova ◽  
Mikko Turunen ◽  
Oliver Mortusewicz ◽  
Teemu Kivioja ◽  
Patrick Herr ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Tumor Cells ◽  
Differential Response ◽  
Cell Cycle Regulators ◽  
Genome Wide

Anticancer Activity of Platinum (II) Complex with 2-Benzoylpyridine by Induction of DNA Damage, S-Phase Arrest, and Apoptosis

2020 ◽  
Vol 20 (4) ◽  
pp. 504-517
Author(s):  
Yu-Lan Li ◽  
Xin-Li Gan ◽  
Rong-Ping Zhu ◽  
Xuehong Wang ◽  
Duan-Fang Liao ◽  
...  
Keyword(s):  
Dna Damage ◽  
B Cell ◽  
Anticancer Activity ◽  
Cancer Cells ◽  
Hepg2 Cells ◽  
Caspase 3 ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
S Phase ◽  
Caspase 9

Objective: To overcome the disadvantages of cisplatin, numerous platinum (Pt) complexes have been prepared. However, the anticancer activity and mechanism of Pt(II) complexed with 2-benzoylpyridine [Pt(II)- Bpy]: [PtCl2(DMSO)L] (DMSO = dimethyl sulfoxide, L = 2-benzoylpyridine) in cancer cells remain unknown. Methods: Pt(II)-Bpy was synthesized and characterized by spectrum analysis. Its anticancer activity and underlying mechanisms were demonstrated at the cellular, molecular, and in vivo levels. Results: Pt(II)-Bpy inhibited tumor cell growth, especially HepG2 human liver cancer cells, with a halfmaximal inhibitory concentration of 9.8±0.5μM, but with low toxicity in HL-7702 normal liver cells. Pt(II)- Bpy induced DNA damage, which was demonstrated through a marked increase in the expression of cleavedpoly (ADP ribose) polymerase (PARP) and gamma-H2A histone family member X and a decrease in PARP expression. The interaction of Pt(II)-Bpy with DNA at the molecular level was most likely through an intercalation mechanism, which might be evidence of DNA damage. Pt(II)-Bpy initiated cell cycle arrest at the S phase in HepG2 cells. It also caused severe loss of the mitochondrial membrane potential; a decrease in the expression of caspase-9 and caspase-3; an increase in reactive oxygen species levels; the release of cytochrome c and apoptotic protease activation factor; and the activation of caspase-9 and caspase-3 in HepG2 cells, which in turn resulted in apoptosis. Meanwhile, changes in p53 and related proteins were observed including the upregulation of p53, the phosphorylation of p53, p21, B-cell lymphoma-2-associated X protein, and NOXA; and the downregulation of B-cell lymphoma 2. Moreover, Pt(II)-Bpy displayed marked inhibitory effects on tumor growth in the HepG2 nude mouse model. Conclusion: Pt(II)-Bpy is a potential candidate for cancer chemotherapy.

scholarly journals Mutations in SID2, a Novel Gene in Saccharomyces cerevisiae, Cause Synthetic Lethality With sic1 Deletion and May Cause a Defect During S Phase

Genetics ◽  
2001 ◽  
Vol 159 (1) ◽  
pp. 17-33
Author(s):  
Matthew D Jacobson ◽  
Claudia X Muñoz ◽  
Kirstin S Knox ◽  
Beth E Williams ◽  
Lenette L Lu ◽  
...  
Keyword(s):  
Dna Damage ◽  
Synthetic Lethality ◽  
S Phase ◽  
Temperature Sensitive ◽  
Replication Forks ◽  
Novel Gene ◽  
Mutant Strains ◽  
Single Nucleus ◽  
2C Dna Content ◽  
Slow Growing

Abstract SIC1 encodes a nonessential B-type cyclin/CDK inhibitor that functions at the G1/S transition and the exit from mitosis. To understand more completely the regulation of these transitions, mutations causing synthetic lethality with sic1Δ were isolated. In this screen, we identified a novel gene, SID2, which encodes an essential protein that appears to be required for DNA replication or repair. sid2-1 sic1Δ strains and sid2-21 temperature-sensitive strains arrest preanaphase as large-budded cells with a single nucleus, a short spindle, and an ~2C DNA content. RAD9, which is necessary for the DNA damage checkpoint, is required for the preanaphase arrest of sid2-1 sic1Δ cells. Analysis of chromosomes in mutant sid2-21 cells by field inversion gel electrophoresis suggests the presence of replication forks and bubbles at the arrest. Deleting the two S phase cyclins, CLB5 and CLB6, substantially suppresses the sid2-1 sic1Δ inviability, while stabilizing Clb5 protein exacerbates the defects of sid2-1 sic1Δ cells. In synchronized sid2-1 mutant strains, the onset of replication appears normal, but completion of DNA synthesis is delayed. sid2-1 mutants are sensitive to hydroxyurea indicating that sid2-1 cells may suffer DNA damage that, when combined with additional insult, leads to a decrease in viability. Consistent with this hypothesis, sid2-1 rad9 cells are dead or very slow growing even when SIC1 is expressed.

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