scholarly journals A link between mitotic defects and mitotic catastrophe: detection and cell fate

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Elena V. Sazonova ◽  
Svetlana V. Petrichuk ◽  
Gelina S. Kopeina ◽  
Boris Zhivotovsky
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Death ◽  
Clinical Practice ◽  
Cell Fate ◽  
Mitotic Catastrophe ◽  
Cell Aging ◽  
Molecular Pathways ◽  
Cycle Arrest ◽  
Different Types

AbstractAlthough the phenomenon of mitotic catastrophe was first described more than 80 years ago, only recently has this term been used to explain a mechanism of cell death linked to delayed mitosis. Several mechanisms have been suggested for mitotic catastrophe development and cell fate. Depending on molecular perturbations, mitotic catastrophe can end in three types of cell death, namely apoptosis, necrosis, or autophagy. Moreover, mitotic catastrophe can be associated with different types of cell aging, the development of which negatively affects tumor elimination and, consequently, reduces the therapeutic effect. The effective triggering of mitotic catastrophe in clinical practice requires induction of DNA damage as well as inhibition of the molecular pathways that regulate cell cycle arrest and DNA repair. Here we discuss various methods to detect mitotic catastrophe, the mechanisms of its development, and the attempts to use this phenomenon in cancer treatment.

scholarly journals RUNX Family Participates in the Regulation of p53-Dependent DNA Damage Response

2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
Toshinori Ozaki ◽  
Akira Nakagawara ◽  
Hiroki Nagase
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Death ◽  
Cell Cycle Arrest ◽  
Dna Damage Response ◽  
Apoptotic Cell ◽  
Genetic Alterations ◽  
Apoptotic Cell Death ◽  
Cycle Arrest ◽  
Damage Response

A proper DNA damage response (DDR), which monitors and maintains the genomic integrity, has been considered to be a critical barrier against genetic alterations to prevent tumor initiation and progression. The representative tumor suppressor p53 plays an important role in the regulation of DNA damage response. When cells receive DNA damage, p53 is quickly activated and induces cell cycle arrest and/or apoptotic cell death through transactivating its target genes implicated in the promotion of cell cycle arrest and/or apoptotic cell death such asp21WAF1,BAX, andPUMA. Accumulating evidence strongly suggests that DNA damage-mediated activation as well as induction of p53 is regulated by posttranslational modifications and also by protein-protein interaction. Loss of p53 activity confers growth advantage and ensures survival in cancer cells by inhibiting apoptotic response required for tumor suppression. RUNX family, which is composed of RUNX1, RUNX2, and RUNX3, is a sequence-specific transcription factor and is closely involved in a variety of cellular processes including development, differentiation, and/or tumorigenesis. In this review, we describe a background of p53 and a functional collaboration between p53 and RUNX family in response to DNA damage.

scholarly journals Involvement of p53 in cell death following cell cycle arrest and mitotic catastrophe induced by rotenone

2011 ◽  
Vol 1813 (3) ◽  
pp. 492-499 ◽  
Author(s):  
António Pedro Gonçalves ◽  
Valdemar Máximo ◽  
Jorge Lima ◽  
Keshav K. Singh ◽  
Paula Soares ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Cell Cycle Arrest ◽  
Mitotic Catastrophe ◽  
Cycle Arrest

Inducible Loss of the Fanconi Anemia Pathway in iPSC Causes Rapid Cell Cycle Arrest and Apoptosis through ATM/ATR and p53 Signaling

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3528-3528
Author(s):  
Timothy M Chlon ◽  
Elizabeth E Hoskins ◽  
Sonya Ruiz-Torres ◽  
Christopher N Mayhew ◽  
Kathryn A Wikenheiser-Brokamp ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Bone Marrow ◽  
Dna Damage ◽  
Cell Death ◽  
Dna Repair ◽  
Cell Cycle Arrest ◽  
Loss Of Function ◽  
Cycle Arrest ◽  
Repair Pathways

Abstract As the source of all cells in the developing embryo proper, embryonic stem cells (ESC) bear the unique responsibility to prevent mutations from being propagated throughout the entire organism and the germ line. It is likely for this reason that ESC and induced pluripotent stem cells (iPSC) maintain a dramatically lower mutation frequency than cultured somatic cells. Multiple mechanisms for this enhanced genomic surveillance have been proposed, including hypersensitivity of DNA damage response signaling pathways and increased activity of error-free DNA repair pathways, such as homologous recombination. However, the effect of loss of function of DNA repair pathways in these cells remains poorly understood. The Fanconi Anemia (FA) pathway is a DNA repair pathway that is required for the repair of DNA interstrand crosslink damage and also promotes repair of DNA double-strand breaks by homologous recombination . Genetic defects in this pathway cause a disease characterized by bone marrow failure and extreme cancer incidence. Several recent studies have revealed that the FA pathway is required for efficient somatic cell reprogramming to iPSC and suggest that FA cells undergo cell death during this process. Another recent study found that the growth of FA patient-specific iPSC was attenuated with a G2/M arrest when compared to control iPSC, suggesting that these cells arrest upon failed DNA repair. In this study, we sought to determine the effects of acute loss of function of the FA pathway in iPSC through the generation of FA patient-derived iPSC with inducible complementation of the defective FA gene. Fibroblasts were cultured from skin biopsies of multiple FA patients and transduced with a lentiviral vector expressing the complementing FA gene product under DOX-inducible control. Cells were then reprogrammed to iPSC using episomal transfection. These cells formed iPSC colonies only when reprogramming was carried out in the presence of DOX, confirming that the FA pathway is required for efficient reprogramming. Once cell lines were obtained, DOX-dependent FA functionality was verified based on FANCD2 monoubiquitination and nuclear focus formation after treatment with DNA damaging agents. We then cultured the iPSC for extended periods of time in the presence and absence of DOX. Interestingly, the cultures underwent profound cell death and cell cycle arrest within 7 days of DOX-withdrawal and completely failed to expand after one passage. EdU cell cycle analysis confirmed cell cycle arrest in the G2/M phase. Furthermore, cleaved caspase 3 staining confirmed that the number of apoptotic cells increased by 3-fold in the -DOX culture. Despite these effects, cells cultured in both the presence and absence of DOX formed teratomas in nude mice, thus indicating the maintenance of full differentiation capacity in the absence of the FA pathway. In order to determine the mechanisms underlying G2/M arrest and cell death, expression of p53 and its target genes was detected by both western blot analysis and qRT-PCR. Only a slight increase in p53 activation was observed by 7 days post DOX-withdrawal. Furthermore, knockdown of p53 resulted in rescue from apoptosis to normal levels but not rescue from cell cycle arrest. Increased ATM and ATR DNA damage sensor kinase activities were also detected in –DOX cells, concominant with increased phosphorylation of the ATM-target Chk2 and reduced abundance of the G2/M checkpoint protein CDC25A. These results reveal hyperactive DNA damage responses upon FA loss which may underlie the attenuated cell cycle progression of FA-iPSC independent of p53. Remarkably, effects in this FA model system appear equivalent to those responsible for the depletion of HSC in the bone marrow of FA patients. Thus, iPSC models may be useful for future studies of the mechanisms underlying FA stem cell arrest and for the development of therapeutics that alleviate these phenotypes. Disclosures No relevant conflicts of interest to declare.

scholarly journals Equivalent effect of DNA damage-induced apoptotic cell death or long-term cell cycle arrest on colon carcinoma cell proliferation and tumour growth

Oncogene ◽  
2005 ◽  
Vol 25 (2) ◽  
pp. 165-175 ◽  
Author(s):  
M R Bhonde ◽  
M-L Hanski ◽  
M Notter ◽  
B F Gillissen ◽  
P T Daniel ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Dna Damage ◽  
Cell Death ◽  
Tumour Growth ◽  
Carcinoma Cell ◽  
Apoptotic Cell ◽  
Cycle Arrest ◽  
Equivalent Effect

scholarly journals BRCA1 Is Required for Maintenance of Phospho-Chk1 and G2/M Arrest during DNA Cross-Link Repair in DT40 Cells

2015 ◽  
Vol 35 (22) ◽  
pp. 3829-3840 ◽  
Author(s):  
Margarethe Draga ◽  
Elizabeth B. Madgett ◽  
Cassandra J. Vandenberg ◽  
David du Plessis ◽  
Aisling Kaufmann ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Death ◽  
Clonogenic Survival ◽  
Repair Pathway ◽  
Cross Link ◽  
Cycle Arrest ◽  
Interstrand Cross Links ◽  
Cross Links ◽  
Dt40 Cells

The Fanconi anemia DNA repair pathway is pivotal for the efficient repair of DNA interstrand cross-links. Here, we show that FA-defective (Fancc−) DT40 cells arrest in G2phase following cross-link damage and trigger apoptosis. Strikingly, cell death was reduced inFancc−cells by additional deletion of the BRCA1 tumor suppressor, resulting in elevated clonogenic survival. Increased resistance to cross-link damage was not due to loss of toxic BRCA1-mediated homologous recombination but rather through the loss of a G2checkpoint. This proapoptotic role also required the BRCA1-A complex member ABRAXAS (FAM175A). Finally, we show that BRCA1 promotes G2arrest and cell death by prolonging phosphorylation of Chk1 on serine 345 after DNA damage to sustain arrest. Our data imply that DNA-induced cross-link death in cells defective in the FA pathway is dependent on the ability of BRCA1 to prolong cell cycle arrest in G2phase.

scholarly journals H2AX Is Required for Cell Cycle Arrest via the p53/p21 Pathway

2009 ◽  
Vol 29 (10) ◽  
pp. 2828-2840 ◽  
Author(s):  
Michalis Fragkos ◽  
Jaana Jurvansuu ◽  
Peter Beard
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Arrest ◽  
Cellular Response ◽  
Replication Fork ◽  
Mitotic Catastrophe ◽  
Adeno Associated Virus ◽  
Cycle Arrest ◽  
And Diffusion

ABSTRACT Phosphorylation of H2AX (γH2AX) is an early sign of DNA damage induced by replication stalling. However, the role of H2AX in the repair of this type of DNA damage is still unclear. In this study, we used an inactivated adeno-associated virus (AAV) to induce a stalled replication fork signal and investigate the function of γH2AX. The cellular response to AAV provides a unique model to study γH2AX function, because the infection causes pannuclear H2AX phosphorylation without any signs of damage to the host genome. We found that pannuclear γH2AX formation is a result of ATR overactivation and diffusion but is independent of ATM. The inhibition of H2AX with RNA interference or the use of H2AX-deficient cells showed that γH2AX is dispensable for the formation and maintenance of DNA repair foci induced by stalled replication. However, in the absence of H2AX, the AAV-containing cells showed proteosome-dependent degradation of p21, followed by caspase-dependent mitotic catastrophe. In contrast, H2AX-proficient cells as well as H2AX-complemented H2AX−/− cells reacted by increasing p21 levels and arresting the cell cycle. The results establish a new role for H2AX in the p53/p21 pathway and indicate that H2AX is required for p21-induced cell cycle arrest after replication stalling.

scholarly journals Marine Invertebrate Extracts Induce Colon Cancer Cell Death via ROS-Mediated DNA Oxidative Damage and Mitochondrial Impairment

Biomolecules ◽  
2019 ◽  
Vol 9 (12) ◽  
pp. 771 ◽  
Author(s):  
Verónica Ruiz-Torres ◽  
Celia Rodríguez-Pérez ◽  
María Herranz-López ◽  
Beatriz Martín-García ◽  
Ana-María Gómez-Caravaca ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Colon Cancer ◽  
Dna Damage ◽  
Cell Death ◽  
Cell Cycle Arrest ◽  
Colon Cancer Cell ◽  
Mitochondrial Depolarization ◽  
Antiproliferative Effects ◽  
Cycle Arrest ◽  
Ros Accumulation

Marine compounds are a potential source of new anticancer drugs. In this study, the antiproliferative effects of 20 invertebrate marine extracts on three colon cancer cell models (HGUE-C-1, HT-29, and SW-480) were evaluated. Extracts from two nudibranchs (Phyllidia varicosa, NA and Dolabella auricularia, NB), a holothurian (Pseudocol ochirus violaceus, PS), and a soft coral (Carotalcyon sp., CR) were selected due to their potent cytotoxic capacities. The four marine extracts exhibited strong antiproliferative effects and induced cell cycle arrest at the G2/M transition, which evolved into early apoptosis in the case of the CR, NA, and NB extracts and necrotic cell death in the case of the PS extract. All the extracts induced, to some extent, intracellular ROS accumulation, mitochondrial depolarization, caspase activation, and DNA damage. The compositions of the four extracts were fully characterized via HPLC-ESI-TOF-MS analysis, which identified up to 98 compounds. We propose that, among the most abundant compounds identified in each extract, diterpenes, steroids, and sesqui- and seterterpenes (CR); cembranolides (PS); diterpenes, polyketides, and indole terpenes (NA); and porphyrin, drimenyl cyclohexanone, and polar steroids (NB) might be candidates for the observed activity. We postulate that reactive oxygen species (ROS) accumulation is responsible for the subsequent DNA damage, mitochondrial depolarization, and cell cycle arrest, ultimately inducing cell death by either apoptosis or necrosis.

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