Regulation of cell cycle arrest and cell death — alternative responses to DNA damage

2021 ◽  
pp. 213-222
Author(s):  
Chris Norbury
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Death ◽  
Cell Cycle Arrest ◽  
Cycle Arrest ◽  
Alternative Responses ◽  
Regulation Of Cell Cycle

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.

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 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

Differences in the Induction of DNA Damage, Cell Cycle Arrest, and Cell Death by 5-Fluorouracil and Antifolates

2001 ◽  
Vol 12 (5) ◽  
pp. 231-239 ◽  
Author(s):  
H.H.J. Backus ◽  
H.M. Pinedo ◽  
D. Wouters ◽  
C.M. Kuiper ◽  
G. Jansen ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Death ◽  
Cell Cycle Arrest ◽  
Damage Cell ◽  
Cycle Arrest

The role of p53 and cell death by apoptosis and necrosis in 4-hydroperoxycyclophosphamide-induced limb malformations

Development ◽  
1998 ◽  
Vol 125 (16) ◽  
pp. 3225-3234
Author(s):  
S.A. Moallem ◽  
B.F. Hales
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Death ◽  
Drug Treatment ◽  
Cell Cycle Arrest ◽  
Wild Type ◽  
Cycle Arrest ◽  
Limb Malformations ◽  
Apoptosis And Necrosis

The exposure of embryonic murine limbs in vitro to an activated analog of cyclophosphamide, 4-hydroperoxycyclophosphamide (4OOH-CPA), induced limb malformations and apoptosis. The purpose of this study was to investigate the role of the tumor suppressor/cell cycle checkpoint gene, p53, and of cell cycle arrest in the response of the limbs to cyclophosphamide. Limbs, excised on day 12 of gestation from wild-type, heterozygous or homozygous p53-knockout transgenic murine embryos, were treated with vehicle (water) or 4OOH-CPA (0.3, 1.0 or 3.0 microgram/ml) and cultured for 6 days. Exposure of wild-type (+/+) limbs to 4OOH-CPA resulted in limb malformations, and reduced limb areas and developmental scores. The homozygous (−/−) limbs were dramatically more sensitive to the effects of 4OOH-CPA, as assessed by limb morphology, area and score. Heterozygous limbs exposed to the drug were intermediate for each parameter. Apoptosis, as assessed by the formation of a DNA ladder, was increased in drug-exposed wild-type limbs, but not in the drug-exposed homozygous limbs. Light and electron microscopy examination of the limbs revealed that drug treatment of wild-type limbs induced the morphological changes typical of apoptosis, particularly in the interdigital regions. In contrast, there was no evidence of apoptosis in homozygous limbs exposed to 4-OOH-CPA; morphological characteristics of necrosis such as cell membrane breakdown, mitochondrial swelling and cellular disintegration were evident throughout these limbs. Heterozygous limbs had cells dying with the characteristics of both apoptosis and necrosis. Fragments of poly(ADP-ribose) polymerase characteristic of necrosis predominated in the drug-treated heterozygous and homozygous limbs. 4-OOH-CPA-treatment of limbs from wild-type embryos led to arrest of the cell cycle at the G1/S phase. No cell cycle arrest was observed after drug treatment of homozygous limbs, in which populations of cells in S and G2/M phases, as well as a population of sub G1 cells, were found. Thus, the presence of p53 and of p53-dependent apoptosis protect organogenesis-stage limbs from insult with a teratogen. The absence of p53 may decrease DNA repair capacity and contribute to the accumulation of DNA damage in limb cells and their daughter cells; the failure of apoptosis to eliminate cells with DNA damage may result in increased cell death by necrosis and major limb malformations.

scholarly journals PS2 - 153 Dianhydrogalactitol (VAL-083) Treatment Causes Irreparable DNA Double-Strand Breaks, S/G2 Phase Cell-Cycle Arrest and Cell Death in Cancer Cells

2016 ◽  
Vol 43 (S4) ◽  
pp. S12-S13
Author(s):  
B. Zhai ◽  
A. Steino ◽  
J. Bacha ◽  
D. Brown ◽  
M. Daugaard
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Death ◽  
Cell Cycle Arrest ◽  
Cancer Cells ◽  
Double Strand Breaks ◽  
Phase Cell ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Cycle Arrest

Dianhydrogalactitol (VAL-083) is a unique bi-functional alkylating agent causing N7-guanine-methylation and inter-strand DNA crosslinks. VAL-083 readily crosses the blood-brain barrier, accumulates in brain tumor tissue and has shown activity in prior NCI-sponsored clinical trials against various cancers, including glioblastoma (GBM) and medulloblastoma. VAL-083 is also active against GBM cancer stem cells and acts as a radiosensitizer independent of O6-methylguanine-DNA methyltransferase activity (in contrast to e.g. temozolomide and BCNU). Here we report new insights into VAL-083 mechanism of action by showing that VAL-083 induces irreversible cell-cycle arrest and cell death caused by replication-dependent DNA damage. In lung (H2122, H1792, H23, A549) and prostate (PC3, LNCaP) cancer cell lines VAL-083 treatment caused irreversible S/G2 cell-cycle arrest and cell death (IC50 range 3.06-25.7 µM). VAL-083 pulse-treatment led to persistent phosphorylation of DNA double-strand breaks (DSB) sensors ATM, single-strand DNA-binding Replication Protein A (RPA32), and histone variant H2A.X, suggesting persistent DNA lesions. After 10 months in culture with increasing VAL-083 concentrations, H1792 and LNCaP cells survive at concentrations up to 9.4 µM and 7.4 µM, respectively, suggesting that efficient resistance mechanisms are not easily acquired by the cancer cells. Taken together with previous results showing that VAL-083 circumvents cisplatin-resistance and is less dependent on p53 activity than cisplatin, these results suggest a molecular mechanism for VAL-083 that differs from both TMZ, BCNU and cisplatin. They further suggest that irreparable DNA damage induced by VAL-083 is impervious to common strategies employed by cancer cells to escape effects of alkylating drugs used in GBM treatment.

Sign in / Sign up

Export Citation Format

Share Document