scholarly journals Checkpoint non-fidelity induces a complex landscape of lineage fitness after DNA damage

2018 ◽  
Author(s):  
Callum J. Campbell ◽  
Ashok R. Venkitaraman ◽  
Alessandro Esposito
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Fate ◽  
Mammalian Cells ◽  
Cell Cycle Progression ◽  
Dna Lesions ◽  
Lineage Tracing ◽  
Cell Cycle Checkpoints ◽  
Complex Landscape ◽  
Cellular Dna

AbstractDNA damage in proliferating mammalian cells causes death1, senescence2 or continued survival, via checkpoints that monitor damage and regulate cell cycle progression, DNA repair and fate determination3. Cell cycle checkpoints facilitate tumour suppression by preventing the generation of proliferating mutated cells4, particularly by blocking passage of DNA lesions into replication and mitosis5. While checkpoint non-fidelity permits cells to carry genomic aberrations into subsequent cell cycle phases6, its long-term consequences on lineages descendant from damaged cells remains poorly characterised. Devising methods for microscopy-based lineage tracing, we unexpectedly demonstrate that transient DNA damage to single living cells bearing a negligent checkpoint induces heterogenous cell-fate outcomes in their descendant generations removed from the initial insult. After transiently damaged cells undergo an initial arrest, pairs of descendant cells without obvious cell-cycle abnormalities either divide or die in a seemingly stochastic way. Progeny of transiently damaged cells may die generations afterwards, creating considerable variability of lineage fitness that promotes overall persistence in a mutagenic environment. Descendants of damaged cells frequently form micronuclei, activating immunogenic signalling. Our findings reveal previously unrecognized, heterogenous effects of cellular DNA damage that manifest long afterwards in descendant cells. We suggest that these heterogenous descendant cell-fate responses may function physiologically to ensure the elimination and immune clearance of damaged cell lineages, but pathologically, may enable the prolonged survival of cells bearing mutagenic damage.

scholarly journals Cellular responses to a prolonged delay in mitosis are determined by a DNA damage response controlled by Bcl-2 family proteins

Open Biology ◽  
2015 ◽  
Vol 5 (3) ◽  
pp. 140156 ◽  
Author(s):  
Didier J. Colin ◽  
Karolina O. Hain ◽  
Lindsey A. Allan ◽  
Paul R. Clarke
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Protein Kinases ◽  
Cell Fate ◽  
Dna Damage Response ◽  
Cell Cycle Progression ◽  
Cycle Progression ◽  
Anti Cancer ◽  
Damage Response ◽  
Microtubule Poisons

Anti-cancer drugs that disrupt mitosis inhibit cell proliferation and induce apoptosis, although the mechanisms of these responses are poorly understood. Here, we characterize a mitotic stress response that determines cell fate in response to microtubule poisons. We show that mitotic arrest induced by these drugs produces a temporally controlled DNA damage response (DDR) characterized by the caspase-dependent formation of γH2AX foci in non-apoptotic cells. Following exit from a delayed mitosis, this initial response results in activation of DDR protein kinases, phosphorylation of the tumour suppressor p53 and a delay in subsequent cell cycle progression. We show that this response is controlled by Mcl-1, a regulator of caspase activation that becomes degraded during mitotic arrest. Chemical inhibition of Mcl-1 and the related proteins Bcl-2 and Bcl-x L by a BH3 mimetic enhances the mitotic DDR, promotes p53 activation and inhibits subsequent cell cycle progression. We also show that inhibitors of DDR protein kinases as well as BH3 mimetics promote apoptosis synergistically with taxol (paclitaxel) in a variety of cancer cell lines. Our work demonstrates the role of mitotic DNA damage responses in determining cell fate in response to microtubule poisons and BH3 mimetics, providing a rationale for anti-cancer combination chemotherapies.

scholarly journals p53 pro-apoptotic activity is regulated by the G2/M promoting factor Cdk1 in response to DNA damage

2021 ◽  
Author(s):  
Mireya Ruiz-Losada ◽  
Raul González ◽  
Ana Peropadre ◽  
Antonio Baonza ◽  
Carlos Estella
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Fate ◽  
Cell Cycle Progression ◽  
P53 Protein ◽  
Genotoxic Stress ◽  
Suppressor Gene ◽  
Cell Fate Decisions ◽  
Apoptotic Activity ◽  
Induced Apoptosis

SummaryExposure to genotoxic stress promotes cell-cycle arrest and DNA repair or apoptosis. These “life” or “death” cell fate decisions often rely on the activity of the tumor suppressor gene p53. Therefore, how p53 activity is precisely regulated is essential to maintain tissue homeostasis and to prevent cancer development. Here we demonstrate that Drosophila p53 pro-apoptotic activity is regulated by the G2/M kinase Cdk1. We find that cell cycle arrested or endocycle-induced cells are refractory to ionizing radiation induced apoptosis. We show that the p53 protein is not able to bind to and to activate the expression of the pro-apoptotic genes in experimentally arrested cells. Our results indicate that p53 genetically and physically interacts with Cdk1 and that p53 pro-apoptotic role is regulated by the cell cycle status of the cell. We propose a model in which cell cycle progression and p53 pro-apoptotic activity are molecularly connected to coordinate the appropriate response after DNA damage.

scholarly journals The DNA Damage-Induced Cell Cycle Checkpoints

2000 ◽  
Vol 2 (4) ◽  
pp. 237-243
Author(s):  
Piotr Widlak
Keyword(s):  
Cell Cycle ◽  
Signal Transduction ◽  
Dna Damage ◽  
Tumor Suppressor ◽  
Cell Cycle Progression ◽  
P53 Protein ◽  
Critical Role ◽  
Cell Cycle Checkpoints ◽  
Signal Transduction Pathways ◽  
Cycle Progression

The proliferation of eukaryotic cells is driven by a process called the cell cycle. Proper regulation of this process, leading to orderly execution of sequential steps within the cycle, ensures normal development and homeostasis of the organism. On the other hand, perturbations of the cell cycle are frequently attributed to cancer cells. Mechanisms that ensure the order and fidelity of events in the cell cycle are called checkpoints. The checkpoints induced by damaged DNA delay the cell cycle progression, providing more time for repair of lesion before DNA replication and segregation. The DNA damage-induced checkpoints can be recognized as signal transduction pathways that communicate information between DNA lesion and components of the cell cycle. Proteins involved in the cell cycle, as well as components of the signal transduction pathways communicating with the cell cycle, are frequently products of oncogenes and tumor suppressor genes. Malfunction of these genes plays a critical role in the development of human cancers. The key component in the checkpoint machinery is tumor suppressor gene p53, involved in either regulation of the cell cycle progression (e.g. Gl arrest of cells treated with DNA damaging factor) or activation of programmed cell death (apoptosis). It is postulated that p53 protein is activated by DNA damage detectors. One of the candidates for this role is DNA-dependent protein kinase (DNA-PK) which recognizes DNA strand breaks and phosphorylates p53 protein.

scholarly journals Molecular Spectroscopic Markers of DNA Damage

Molecules ◽  
2020 ◽  
Vol 25 (3) ◽  
pp. 561 ◽  
Author(s):  
Kamila Sofińska ◽  
Natalia Wilkosz ◽  
Marek Szymoński ◽  
Ewelina Lipiec
Keyword(s):  
Dna Damage ◽  
Mammalian Cells ◽  
Living Organism ◽  
Eukaryotic Cell ◽  
Dna Lesions ◽  
Spectral Signature ◽  
Dna Solutions ◽  
Using Data ◽  
Cellular Dna ◽  
Physical And Chemical

Every cell in a living organism is constantly exposed to physical and chemical factors which damage the molecular structure of proteins, lipids, and nucleic acids. Cellular DNA lesions are the most dangerous because the genetic information, critical for the identity and function of each eukaryotic cell, is stored in the DNA. In this review, we describe spectroscopic markers of DNA damage, which can be detected by infrared, Raman, surface-enhanced Raman, and tip-enhanced Raman spectroscopies, using data acquired from DNA solutions and mammalian cells. Various physical and chemical DNA damaging factors are taken into consideration, including ionizing and non-ionizing radiation, chemicals, and chemotherapeutic compounds. All major spectral markers of DNA damage are presented in several tables, to give the reader a possibility of fast identification of the spectral signature related to a particular type of DNA damage.

scholarly journals Deubiquitylation and stabilization of p21 by USP11 is critical for cell-cycle progression and DNA damage responses

2018 ◽  
Vol 115 (18) ◽  
pp. 4678-4683 ◽  
Author(s):  
Tanggang Deng ◽  
Guobei Yan ◽  
Xin Song ◽  
Lin Xie ◽  
Yu Zhou ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Fate ◽  
Cell Cycle Progression ◽  
Kinase Inhibitor ◽  
Independent Manner ◽  
Cycle Progression ◽  
Dna Damage Responses ◽  
Fate Decision

p21WAF1/CIP1 is a broad-acting cyclin-dependent kinase inhibitor. Its stability is essential for proper cell-cycle progression and cell fate decision. Ubiquitylation by the multiple E3 ubiquitin ligase complexes is the major regulatory mechanism of p21, which induces p21 degradation. However, it is unclear whether ubiquitylated p21 can be recycled. In this study, we report USP11 as a deubiquitylase of p21. In the nucleus, USP11 binds to p21, catalyzes the removal of polyubiquitin chains conjugated onto p21, and stabilizes p21 protein. As a result, USP11 reverses p21 polyubiquitylation and degradation mediated by SCFSKP2, CRL4CDT2, and APC/CCDC20 in a cell-cycle–independent manner. Loss of USP11 causes the destabilization of p21 and induces the G1/S transition in unperturbed cells. Furthermore, p21 accumulation mediated by DNA damage is completely abolished in cells depleted of USP11, which results in abrogation of the G2 checkpoint and induction of apoptosis. Functionally, USP11-mediated stabilization of p21 inhibits cell proliferation and tumorigenesis in vivo. These findings reveal an important mechanism by which p21 can be stabilized by direct deubiquitylation, and they pinpoint a crucial role of the USP11-p21 axis in regulating cell-cycle progression and DNA damage responses.

scholarly journals Coordination between cell proliferation and apoptosis after DNA damage in Drosophila

2021 ◽  
Author(s):  
Mireya Ruiz-Losada ◽  
Raul González ◽  
Ana Peropadre ◽  
Alejandro Gil-Gálvez ◽  
Juan J. Tena ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Fate ◽  
Cell Cycle Progression ◽  
Genotoxic Stress ◽  
Regulatory Elements ◽  
Suppressor Gene ◽  
Cycle Progression ◽  
Cell Fate Decisions ◽  
Induced Apoptosis

AbstractExposure to genotoxic stress promotes cell cycle arrest and DNA repair or apoptosis. These “life” or “death” cell fate decisions often rely on the activity of the tumor suppressor gene p53. Therefore, the precise regulation of p53 is essential to maintain tissue homeostasis and to prevent cancer development. However, how cell cycle progression has an impact on p53 cell fate decision-making is mostly unknown. In this work, we demonstrate that Drosophila p53 proapoptotic activity can be impacted by the G2/M kinase Cdk1. We find that cell cycle arrested or endocycle-induced cells are refractory to ionizing radiation-induced apoptosis. We show that p53 binding to the regulatory elements of the proapoptotic genes and its ability to activate their expression is compromised in experimentally arrested cells. Our results indicate that p53 genetically and physically interacts with Cdk1 and that p53 proapoptotic role is regulated by the cell cycle status of the cell. We propose a model in which cell cycle progression and p53 proapoptotic activity are molecularly connected to coordinate the appropriate response after DNA damage.

scholarly journals hMOF Histone Acetyltransferase Is Required for Histone H4 Lysine 16 Acetylation in Mammalian Cells

2005 ◽  
Vol 25 (15) ◽  
pp. 6798-6810 ◽  
Author(s):  
Mikko Taipale ◽  
Stephen Rea ◽  
Karsten Richter ◽  
Ana Vilar ◽  
Peter Lichter ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Mammalian Cells ◽  
Cell Cycle Progression ◽  
Spectrometric Analysis ◽  
Histone H4 ◽  
Protein Levels ◽  
Γh2ax Foci ◽  
Damage Response

ABSTRACT Reversible histone acetylation plays an important role in regulation of chromatin structure and function. Here, we report that the human orthologue of Drosophila melanogaster MOF, hMOF, is a histone H4 lysine K16-specific acetyltransferase. hMOF is also required for this modification in mammalian cells. Knockdown of hMOF in HeLa and HepG2 cells causes a dramatic reduction of histone H4K16 acetylation as detected by Western blot analysis and mass spectrometric analysis of endogenous histones. We also provide evidence that, similar to the Drosophila dosage compensation system, hMOF and hMSL3 form a complex in mammalian cells. hMOF and hMSL3 small interfering RNA-treated cells also show dramatic nuclear morphological deformations, depicted by a polylobulated nuclear phenotype. Reduction of hMOF protein levels by RNA interference in HeLa cells also leads to accumulation of cells in the G2 and M phases of the cell cycle. Treatment with specific inhibitors of the DNA damage response pathway reverts the cell cycle arrest caused by a reduction in hMOF protein levels. Furthermore, hMOF-depleted cells show an increased number of phospho-ATM and γH2AX foci and have an impaired repair response to ionizing radiation. Taken together, our data show that hMOF is required for histone H4 lysine 16 acetylation in mammalian cells and suggest that hMOF has a role in DNA damage response during cell cycle progression.

scholarly journals Deubiquitylation and stabilization of p21 by USP11 is critical for cell cycle progression and DNA damage responses

2017 ◽  
Author(s):  
Tanggang Deng ◽  
Guobei Yan ◽  
Yu Zhou ◽  
Xiaoxiao Hu ◽  
Jianglin Li ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Fate ◽  
Cell Cycle Progression ◽  
Kinase Inhibitor ◽  
Independent Manner ◽  
Cycle Progression ◽  
Dna Damage Responses ◽  
Fate Decision

Abstractp21WAF1/CIP1is a broad-acting cyclin-dependent kinase inhibitor. Its stability is essential for proper cell cycle progression and cell fate decision. Ubiquitylation by the multiple E3 ubiquitin ligases complex is the major regulatory mechanism of p21, which induces p21 degradation. However, it is unclear whether ubiquitylated p21 can be recycled. In this study, we report USP11 as a deubiquitylase of p21. In the nucleus, USP11 binds to p21, catalyzes the removal of polyubiquitin chains conjugated onto p21 and stabilizes p21 protein. As a result, USP11 reverses p21 polyubiquitylation and degradation mediated by SCFSKP2, CRL4CDT2and APC/CCDT20in a cell cycle-independent manner. Loss of USP11 causes the destabilization of p21 and induces the G1/S transition in unperturbed cells. Furthermore, p21 accumulation mediated by DNA damage is completely abolished in cells depleted of USP11, which results in abrogation of the G2 checkpoint and induction of apoptosis. Functionally, USP11-mediated stabilization of p21 inhibits cell proliferation and tumorigenesis in vivo. These findings reveal an important mechanism by which p21 can be stabilized by direct deubiquitylation and pinpoint a crucial role of the USP11-p21 axis in regulating cell cycle progression and DNA damage responses.

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