Induction of mitotic cell death and cell cycle arrest by spindle disruption and premature entry into mitosis after DNA damage

2007 ◽  
Author(s):  
Ying Wai Chan
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Death ◽  
Cell Cycle Arrest ◽  
Mitotic Cell ◽  
Cycle Arrest

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 CDC44: a putative nucleotide-binding protein required for cell cycle progression that has homology to subunits of replication factor C.

1994 ◽  
Vol 14 (1) ◽  
pp. 255-267 ◽  
Author(s):  
E A Howell ◽  
M A McAlear ◽  
D Rose ◽  
C Holm
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Arrest ◽  
Large Subunit ◽  
Mitotic Cell ◽  
Predicted Amino Acid Sequence ◽  
Replication Factor C ◽  
Replication Factor ◽  
Cycle Arrest ◽  
Factor C

To investigate the means by which a cell regulates the progression of the mitotic cell cycle, we characterized cdc44, a mutation that causes Saccharomyces cerevisiae cells to arrest before mitosis. CDC44 encodes a 96-kDa basic protein with significant homology to a human protein that binds DNA (PO-GA) and to three subunits of human replication factor C (also called activator 1). The hypothesis that Cdc44p is involved in DNA metabolism is supported by the observations that (i) levels of mitotic recombination suggest elevated rates of DNA damage in cdc44 mutants and (ii) the cell cycle arrest observed in cdc44 mutants is alleviated by the DNA damage checkpoint mutations rad9, mec1, and mec2. The predicted amino acid sequence of Cdc44p contains GTPase consensus sites, and mutations in these regions cause a conditional cell cycle arrest. Taken together, these observations suggest that the essential CDC44 gene may encode the large subunit of yeast replication factor C.

CDC44: a putative nucleotide-binding protein required for cell cycle progression that has homology to subunits of replication factor C

1994 ◽  
Vol 14 (1) ◽  
pp. 255-267
Author(s):  
E A Howell ◽  
M A McAlear ◽  
D Rose ◽  
C Holm
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Arrest ◽  
Large Subunit ◽  
Mitotic Cell ◽  
Predicted Amino Acid Sequence ◽  
Replication Factor C ◽  
Replication Factor ◽  
Cycle Arrest ◽  
Factor C

To investigate the means by which a cell regulates the progression of the mitotic cell cycle, we characterized cdc44, a mutation that causes Saccharomyces cerevisiae cells to arrest before mitosis. CDC44 encodes a 96-kDa basic protein with significant homology to a human protein that binds DNA (PO-GA) and to three subunits of human replication factor C (also called activator 1). The hypothesis that Cdc44p is involved in DNA metabolism is supported by the observations that (i) levels of mitotic recombination suggest elevated rates of DNA damage in cdc44 mutants and (ii) the cell cycle arrest observed in cdc44 mutants is alleviated by the DNA damage checkpoint mutations rad9, mec1, and mec2. The predicted amino acid sequence of Cdc44p contains GTPase consensus sites, and mutations in these regions cause a conditional cell cycle arrest. Taken together, these observations suggest that the essential CDC44 gene may encode the large subunit of yeast replication factor C.

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 A RAD9-dependent cell cycle arrest in response to unresolved recombination intermediates in Saccharomyces cerevisiae

2019 ◽  
Author(s):  
Hardeep Kaur ◽  
GN Krishnaprasad ◽  
Michael Lichten
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Cell Cycle ◽  
Dna Damage ◽  
Cell Division ◽  
Cell Cycle Arrest ◽  
Mitotic Cell ◽  
Cycle Arrest ◽  
Associated Lesions

AbstractIn Saccharomyces cerevisiae, the conserved Sgs1-Top3-Rmi1 helicase-decatenase regulates homologous recombination by limiting accumulation of recombination intermediates that are precursors of crossovers. In vitro studies have suggested that the dissolution of double-Holliday junction joint molecules by Sgs1-driven convergent junction migration and Top3-Rmi1 mediated strand decatenation could be responsible for this. To ask if dissolution occurs in vivo, we conditionally depleted Sgs1 and/or Rmi1 during return to growth, a procedure where recombination intermediates formed during meiosis are resolved when cells resume the mitotic cell cycle. Sgs1 depletion during return to growth delayed joint molecule resolution, but ultimately most were resolved and cells divided normally. In contrast, Rmi1 depletion resulted in delayed and incomplete joint molecule resolution, and most cells did not divide. rad9Δ mutation restored cell division in Rmi1-depleted cells, indicating that the DNA damage checkpoint caused this cell cycle arrest. Restored cell division in rad9Δ, Rmi1-depleted cells frequently produced anucleate cells, consistent with the suggestion that persistent recombination intermediates prevented chromosome segregation. Our findings indicate that Sgs1-Top3-Rmi1 acts in vivo, as it does in vitro, to promote recombination intermediate resolution by dissolution. They also indicate that, in the absence of Top3-Rmi1 activity, unresolved recombination intermediates persist and activate the DNA damage response, which is usually thought to be activated by much earlier DNA damage-associated lesions.

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.

Apigenin induces autophagic cell death in human papillary thyroid carcinoma BCPAP cells

2015 ◽  
Vol 6 (11) ◽  
pp. 3464-3472 ◽  
Author(s):  
Li Zhang ◽  
Xian Cheng ◽  
Yanyan Gao ◽  
Jie Zheng ◽  
Qiang Xu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Death ◽  
Papillary Thyroid Carcinoma ◽  
Thyroid Carcinoma ◽  
Cell Cycle Arrest ◽  
Autophagic Cell Death ◽  
Ros Generation ◽  
Papillary Thyroid ◽  
Cycle Arrest

Apigenin-induced autophagic cell death in human papillary thyroid carcinoma BCPAP cells is associated with ROS generation, DNA damage and cell cycle arrest.

scholarly journals Bersaldegenin-1,3,5-orthoacetate induces caspase-independent cell death, DNA damage and cell cycle arrest in human cervical cancer HeLa cells

2021 ◽  
Vol 59 (1) ◽  
pp. 54-65
Author(s):  
Justyna Stefanowicz-Hajduk ◽  
Magdalena Gucwa ◽  
Barbara Moniuszko-Szajwaj ◽  
Anna Stochmal ◽  
Anna Kawiak ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cervical Cancer ◽  
Dna Damage ◽  
Cell Death ◽  
Cell Cycle Arrest ◽  
Hela Cells ◽  
Cycle Arrest ◽  
Human Cervical Cancer
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