scholarly journals Recruitment of 9-1-1 to sites of DNA damage through cell cycle-dependent processing of DNA lesions

Cell Cycle ◽  
2009 ◽  
Vol 8 (13) ◽  
pp. 1979-1983
Author(s):  
Nicholas D. Lakin
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Dna Lesions ◽  
Cycle Dependent

scholarly journals The Interactions of DNA Repair, Telomere Homeostasis, and p53 Mutational Status in Solid Cancers: Risk, Prognosis, and Prediction

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 479
Author(s):  
Pavel Vodicka ◽  
Ladislav Andera ◽  
Alena Opattova ◽  
Ludmila Vodickova
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Dna Repair ◽  
Dna Lesions ◽  
Cell Cycle Checkpoint ◽  
Solid Cancer ◽  
Genomic Integrity ◽  
Repair Capacity ◽  
Mutational Status ◽  
Telomere Homeostasis

The disruption of genomic integrity due to the accumulation of various kinds of DNA damage, deficient DNA repair capacity, and telomere shortening constitute the hallmarks of malignant diseases. DNA damage response (DDR) is a signaling network to process DNA damage with importance for both cancer development and chemotherapy outcome. DDR represents the complex events that detect DNA lesions and activate signaling networks (cell cycle checkpoint induction, DNA repair, and induction of cell death). TP53, the guardian of the genome, governs the cell response, resulting in cell cycle arrest, DNA damage repair, apoptosis, and senescence. The mutational status of TP53 has an impact on DDR, and somatic mutations in this gene represent one of the critical events in human carcinogenesis. Telomere dysfunction in cells that lack p53-mediated surveillance of genomic integrity along with the involvement of DNA repair in telomeric DNA regions leads to genomic instability. While the role of individual players (DDR, telomere homeostasis, and TP53) in human cancers has attracted attention for some time, there is insufficient understanding of the interactions between these pathways. Since solid cancer is a complex and multifactorial disease with considerable inter- and intra-tumor heterogeneity, we mainly dedicated this review to the interactions of DNA repair, telomere homeostasis, and TP53 mutational status, in relation to (a) cancer risk, (b) cancer progression, and (c) cancer therapy.

scholarly journals Differentiating life and death: An inflammatory affair

2018 ◽  
Author(s):  
Dustin Lane
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Death ◽  
Cell Differentiation ◽  
Programmed Cell Death ◽  
Signaling Networks ◽  
Inhibitors Of Apoptosis ◽  
Life And Death ◽  
Cell Death Signaling ◽  
Cycle Dependent

Programmed cell death signaling networks are frequently activated to coordinate the process of cell differentiation, and a variety of apoptotic events can mediate the process. This can include the ligation of death receptors, the activation of downstream caspases, and the induction of chromatin fragmentation, and all of these events can occur without downstream induction of death. Importantly, regulators of programmed cell death also have established roles in mediating differentiation. This review will provide an overview of apoptosis and its regulation by Inhibitors of Apoptosis (IAPs) and Bcl-2 family members. It will then outline the cross-talk between NF-ĸB and apoptotic signaling in the regulation of apoptosis before discussing the function of these regulators in the control of cell differentiation. It will end on a discussion of how a DNA damage-directed, cell cycle-dependent differentiation program may be controlled across multiple passages through cell cycle, and will assert that the failure to properly differentiate is the underlying cause of cancer.

scholarly journals Recruitment of DNA Damage Checkpoint Proteins to Damage in Transcribed and Nontranscribed Sequences

2006 ◽  
Vol 26 (1) ◽  
pp. 39-49 ◽  
Author(s):  
Guochun Jiang ◽  
Aziz Sancar
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Excision Repair ◽  
Dna Lesions ◽  
Human Cells ◽  
Dna Damage Checkpoint ◽  
Damage Site ◽  
Checkpoint Response ◽  
Checkpoint Proteins ◽  
Transcription Complexes

ABSTRACT We developed a chromatin immunoprecipitation method for analyzing the binding of repair and checkpoint proteins to DNA base lesions in any region of the human genome. Using this method, we investigated the recruitment of DNA damage checkpoint proteins RPA, Rad9, and ATR to base damage induced by UV and acetoxyacetylaminofluorene in transcribed and nontranscribed regions in wild-type and excision repair-deficient human cells in G1 and S phases of the cell cycle. We find that all 3 damage sensors tested assemble at the site or in the vicinity of damage in the absence of DNA replication or repair and that transcription enhances recruitment of checkpoint proteins to the damage site. Furthermore, we find that UV irradiation of human cells defective in excision repair leads to phosphorylation of Chk1 kinase in both G1 and S phase of the cell cycle, suggesting that primary DNA lesions as well as stalled transcription complexes may act as signals to initiate the DNA damage checkpoint response.

scholarly journals Cell cycle-dependent processing of DNA lesions controls localization of Rad9 to sites of genotoxic stress

Cell Cycle ◽  
2009 ◽  
Vol 8 (11) ◽  
pp. 1765-1774 ◽  
Author(s):  
Daniël O. Warmerdam ◽  
Raimundo Freire ◽  
Roland Kanaar ◽  
Veronique A.J. Smits
Keyword(s):  
Cell Cycle ◽  
Genotoxic Stress ◽  
Dna Lesions ◽  
Cycle Dependent

Abstract 239: p53 Protects Cardiac Stem Cells From the Toxic Effects of Chemotherapy and Controls their Fate

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Ramaswamy Kannappan ◽  
Giorgia Palano ◽  
Polina Goichberg ◽  
Fumihiro Sanada ◽  
Sergio Signore ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Dna Damage ◽  
Dna Repair ◽  
Critical Role ◽  
Dna Lesions ◽  
Toxic Effects ◽  
Cardiac Stem Cells ◽  
Inhibition Of Proliferation ◽  
P53 Expression

Doxorubicin (DOXO) causes dilated cardiomyopathy and heart failure. We have documented previously that DOXO-mediated cardiotoxicity is dictated by functional alterations of cardiac stem cells (CSCs). DOXO-induced myopathy was coupled with a reduction in CSC number due to increased death, inhibition of proliferation, and senescence. We raised the possibility that survival and growth of CSCs following DOXO treatment may be enhanced by modulating the intracellular level of p53, which plays a critical role in the determination of stem cell fate. For this purpose, transgenic mice carrying an additional p53 allele (Sp53) were studied. With respect to wild-type mice (WT), CSCs isolated from Sp53 mice (Sp53-CSCs) showed increased apoptosis with accumulation of the pro-apoptotic p53 targets BAX, PUMA and Pidd. Conversely, the expression of p21Cip1, a cell cycle inhibitor and inducer of cell senescence, was lower in Sp53-CSCs than WT cells. Upon DOXO treatment, Sp53-CSCs exhibited accelerated onset of apoptosis. However, viable Sp53-CSCs showed enhanced formation of DNA damage response foci, indicative of a very efficient DNA repair mechanism. Following removal of DOXO, Sp53-CSCs re-entered the cell cycle and divided, while WT cells continued to die by apoptosis or became senescent. The response of WT-CSCs to DOXO involved the pro-apoptotic Bcl2 family member Noxa and the senescence-associated protein p16INK4a. In contrast, exposure of Sp53-CSCs to DOXO provoked pulses of p53 expression, which favored sustained upregulation of Mdm2. Mdm2 antagonized the inhibitory effect of p53 on cell growth and prevented apoptosis. Ultimately, Sp53-CSCs showed accumulation of PCNA, which is required for DNA repair and synthesis. Importantly, IGF-1 release was higher in Sp53-CSCs, promoting their replication through an autocrine-paracrine mechanism. Collectively, our data demonstrate that changes in the pattern of p53 expression have beneficial effects on CSCs by amplifying the DNA repair response, facilitating the clearance of cells with non-repairable DNA damage, and enabling the proliferation of cells in which DNA lesions are effectively removed. Thus, targeting p53 expression in CSCs may protect the heart from the toxic effects of chemotherapy.

A Role for NIPA in DNA Damage Response.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1265-1265
Author(s):  
Christine von Klitzing ◽  
Florian Bassermann ◽  
Stephan W. Morris ◽  
Christian Peschel ◽  
Justus Duyster
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Phosphorylation Site ◽  
Genotoxic Stress ◽  
S Phase ◽  
Damage Response ◽  
A Cell ◽  
Cycle Dependent

Abstract The nuclear interaction partner of ALK (NIPA) is a nuclear protein identified by our group in a screen for NPM-ALK interaction partners. We recently reported that NIPA is an F-box protein that assembles with SKP1, Cul1 and Roc1 to establish a novel SCF-type E3 ubiquitin ligase. The formation of the SCFNIPA complex is regulated by cell cycle-dependent phosphorylation of NIPA that restricts SCFNIPA assembly from G1- to late S-phase, thus allowing its substrates to be active from late S-phase throughout mitosis. Proteins involved in cell cycle regulation frequently play a role in DNA damage checkpoints. We therefore sought to determine whether NIPA has a function in the cellular response to genotoxic stress. For this reason we treated NIH/3T3 cells with various DNA-damaging agents. Surprisingly, we observed phosphorylation of NIPA in response to some of these agents, including UV radiation. This phosphorylation was cell cycle phase independent and thus independent of the physiological cell cycle dependent phosphorylation of NIPA. The relevant phosphorylation site is identical to the respective site in the course of cell cycle-dependent phosphorylation of NIPA. Thus, phosphorylation of NIPA upon genotoxic stress would inactivate the SCFNIPA complex in a cell cycle independent manner. Interestingly, this phosphorylation site lies within a consensus site of the Chk1/Chk2 checkpoint kinases. These kinases are central to DNA damage checkpoint signaling. Chk1 is activated by ATR in response to blocked replication forks as they occur after treatment with UV. We performed experiments using the ATM/ATR inhibitor caffeine and the Chk1 inhibitor SB218078 to investigate a potential role of Chk1 in NIPA phosphorylation. Indeed, we found both inhibitors to prevent UV-induced phosphorylation of NIPA. Current experiments applying Chk1 knock-out cells will unravel the role of Chk1 in NIPA phosphorylation. Additional experiments were performed to investigate a function for NIPA in DNA-damage induced apoptosis. In this regard, we observed overexpression of NIPA WT to induce apoptosis in response to UV, whereas no proapoptotic effect was seen with the phosphorylation deficient NIPA mutant. Therefore, the phosphorylated form of NIPA may be involved in apoptotic signaling pathways. In summary, we present data suggesting a cell cycle independent function for NIPA. This activity is involved in DNA damage response and may be involved in regulating apoptosis upon genotoxic stress.

Distinct kinetics of DNA repair protein accumulation at DNA lesions and cell cycle-dependent formation of γH2AX- and NBS1-positive repair foci

2015 ◽  
Vol 107 (12) ◽  
pp. 440-454 ◽  
Author(s):  
Jana Suchánková ◽  
Stanislav Kozubek ◽  
Soňa Legartová ◽  
Petra Sehnalová ◽  
Thomas Küntziger ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Repair ◽  
Dna Lesions ◽  
Protein Accumulation ◽  
Repair Protein ◽  
Dna Repair Protein ◽  
Cycle Dependent ◽  
Kinetics Of

scholarly journals Cell cycle-dependent formation of Cdc45-Claspin complexes in human cells is compromized by UV-mediated DNA damage

FEBS Journal ◽  
2013 ◽  
Vol 280 (19) ◽  
pp. 4888-4902 ◽  
Author(s):  
Ronan Broderick ◽  
Michael D. Rainey ◽  
Corrado Santocanale ◽  
Heinz P. Nasheuer
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Human Cells ◽  
Cycle Dependent

scholarly journals A Tel1/MRX-Dependent Checkpoint Inhibits the Metaphase-to-Anaphase Transition after UV Irradiation in the Absence of Mec1

2004 ◽  
Vol 24 (23) ◽  
pp. 10126-10144 ◽  
Author(s):  
Michela Clerici ◽  
Veronica Baldo ◽  
Davide Mantiero ◽  
Francisca Lottersberger ◽  
Giovanna Lucchini ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Uv Irradiation ◽  
Structural Changes ◽  
Spindle Assembly Checkpoint ◽  
Dna Lesions ◽  
Cycle Phase ◽  
Primary Role ◽  
Atm Kinase ◽  
Checkpoint Kinases

ABSTRACT In Saccharomyces cerevisiae, Mec1/ATR plays a primary role in sensing and transducing checkpoint signals in response to different types of DNA lesions, while the role of the Tel1/ATM kinase in DNA damage checkpoints is not as well defined. We found that UV irradiation in G1 in the absence of Mec1 activates a Tel1/MRX-dependent checkpoint, which specifically inhibits the metaphase-to-anaphase transition. Activation of this checkpoint leads to phosphorylation of the downstream checkpoint kinases Rad53 and Chk1, which are required for Tel1-dependent cell cycle arrest, and their adaptor Rad9. The spindle assembly checkpoint protein Mad2 also partially contributes to the G2/M arrest of UV-irradiated mec1Δ cells independently of Rad53 phosphorylation and activation. The inability of UV-irradiated mec1Δ cells to undergo anaphase can be relieved by eliminating the anaphase inhibitor Pds1, whose phosphorylation and stabilization in these cells depend on Tel1, suggesting that Pds1 persistence may be responsible for the inability to undergo anaphase. Moreover, while UV irradiation can trigger Mec1-dependent Rad53 phosphorylation and activation in G1- and G2-arrested cells, Tel1-dependent checkpoint activation requires entry into S phase independently of the cell cycle phase at which cells are UV irradiated, and it is decreased when single-stranded DNA signaling is affected by the rfa1-t11 allele. This indicates that UV-damaged DNA molecules need to undergo structural changes in order to activate the Tel1-dependent checkpoint. Active Clb-cyclin-dependent kinase 1 (CDK1) complexes also participate in triggering this checkpoint and are required to maintain both Mec1- and Tel1-dependent Rad53 phosphorylation, suggesting that they may provide critical phosphorylation events in the DNA damage checkpoint cascade.

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