scholarly journals Spotting new DNA damage-responsive chromatin-binding proteins

2005 ◽  
Vol 388 (1) ◽  
Author(s):  
Benjamin N. WARDLEWORTH ◽  
Jessica A. DOWNS
Keyword(s):  
Dna Damage ◽  
Transcriptional Activation ◽  
Cellular Response ◽  
Cycle Arrest ◽  
Biochemical Journal ◽  
Proteomics Approach ◽  
Repair Mechanisms ◽  
Comprehensive Picture ◽  
Nuclear Ribonucleoprotein ◽  
Multicellular Organisms

In response to DNA damage, cells initiate multiple repair mechanisms that all contribute to the survival of both the cell and the organism. These responses are numerous and variable, and can include cell cycle arrest, transcriptional activation of DNA repair genes and relocalization of repair proteins to sites of DNA damage. If all else fails, in multicellular organisms the initiation of apoptosis is also a potential cellular response to DNA damage. Despite a wealth of information about these events, it is clear that we do not yet have a comprehensive picture of the cellular responses to DNA damage. In this issue of the Biochemical Journal, a proteomics approach was used by Lee et al. to identify proteins that bind to chromatin in a DNA damage-inducible manner. The proteins identified, nucleophosmin, hnRNP C1 (heterogeneous nuclear ribonucleoprotein C1) and hnRNP C2, were proteins that would not necessarily have been predicted to behave this way. These studies have the potential to be extended and contribute to our knowledge of the cellular response to DNA damage.

scholarly journals A proteomics approach for the identification of nucleophosmin and heterogeneous nuclear ribonucleoprotein C1/C2 as chromatin-binding proteins in response to DNA double-strand breaks

2005 ◽  
Vol 388 (1) ◽  
pp. 7-15 ◽  
Author(s):  
Seung Yun LEE ◽  
Ji-Hye PARK ◽  
Sungsu KIM ◽  
Eun-Jung PARK ◽  
Yungdae YUN ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Binding Proteins ◽  
Double Strand Breaks ◽  
Nuclear Proteins ◽  
Chromatin Binding ◽  
Strand Breaks ◽  
Heterogeneous Nuclear Ribonucleoprotein ◽  
Proteomics Approach ◽  
Nuclear Ribonucleoprotein

Double-strand breaks (DSBs) of chromosomal DNA trigger the cellular response that activates the pathways for DNA repair and cell-cycle checkpoints, and sometimes the pathways leading to cell death if the damage is too severe to be tolerated. Evidence indicates that, upon generation of DNA DSBs, many nuclear proteins that are involved in DNA repair and checkpoints are recruited to chromatin around the DNA lesions. In the present study we used a proteomics approach to identify DNA-damage-induced chromatin-binding proteins in a systematic way. Two-dimensional gel analysis for protein extracts of chromatin from DNA-damage-induced and control HeLa cells identified four proteins as the candidates for DNA-damage-induced chromatin-binding proteins. MALDI–TOF (matrix-assisted laser-desorption ionization–time-of-flight) MS analysis identified these proteins to be NPM (nucleophosmin), hnRNP (heterogeneous nuclear ribonucleoprotein) C1, hnRNP C2 and 37-kDa laminin-receptor precursor, and the identity of these proteins was further confirmed by immunoblot analysis with specific antibodies. We then demonstrated with chromatin-binding assays that NPM and hnRNP C1/C2, the abundant nuclear proteins with pleiotropic functions, indeed bind to chromatin in a DNA-damage-dependent manner, implicating these proteins in DNA repair and/or damage response. Immunofluorescence experiments showed that NPM, normally present in the nucleoli, is mobilized into the nucleoplasm after DNA damage, and that neither NPM nor hnRNP C1/C2 is actively recruited to the sites of DNA breaks. These results suggest that NPM and hnRNP C1/C2 may function at the levels of the global context of chromatin, rather than by specifically targeting the broken DNA.

scholarly journals Ubiquitylation, neddylation and the DNA damage response

Open Biology ◽  
2015 ◽  
Vol 5 (4) ◽  
pp. 150018 ◽  
Author(s):  
Jessica S. Brown ◽  
Stephen P. Jackson
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Cellular Response ◽  
Dna Double Strand Breaks ◽  
Post Translational Modification ◽  
Strand Breaks ◽  
Damage Sensing ◽  
Damage Response ◽  
Repair Mechanisms ◽  
And Function

Failure of accurate DNA damage sensing and repair mechanisms manifests as a variety of human diseases, including neurodegenerative disorders, immunodeficiency, infertility and cancer. The accuracy and efficiency of DNA damage detection and repair, collectively termed the DNA damage response (DDR), requires the recruitment and subsequent post-translational modification (PTM) of a complex network of proteins. Ubiquitin and the ubiquitin-like protein (UBL) SUMO have established roles in regulating the cellular response to DNA double-strand breaks (DSBs). A role for other UBLs, such as NEDD8, is also now emerging. This article provides an overview of the DDR, discusses our current understanding of the process and function of PTM by ubiquitin and NEDD8, and reviews the literature surrounding the role of ubiquitylation and neddylation in DNA repair processes, focusing particularly on DNA DSB repair.

scholarly journals Differential activation of target cellular promoters by p53 mutants with impaired apoptotic function.

1996 ◽  
Vol 16 (9) ◽  
pp. 4952-4960 ◽  
Author(s):  
R L Ludwig ◽  
S Bates ◽  
K H Vousden
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Dna Sequences ◽  
Transcriptional Activation ◽  
Cellular Response ◽  
Kinase Inhibitor ◽  
Cell Types ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Cycle Arrest ◽  
P53 Tumor Suppressor Protein

The p53 tumor suppressor protein is a sequence-specific transcriptional activator, a function which contributes to cell cycle arrest and apoptosis induced by p53 in appropriate cell types. Analysis of a series of p53 point mutants has revealed the potential for selective loss of the ability to transactivate some, but not all, cellular p53-responsive promoters. p53 175P and p53 181L are tumor-derived p53 point mutants which were previously characterized as transcriptionally active. Both mutants retained the ability to activate expression of the cyclin-dependent kinase inhibitor p2lcip1/waf1, and this activity correlated with the ability to induce a G1 cell cycle arrest. However, an extension of this survey to include other p53 targets showed that p53 175P was defective in the activation of p53-responsive sequences derived from the bax promoter and the insulin-like growth factor-binding protein 3 gene (IGF-BP3) promoter, while p53 181L showed loss of the ability to activate a promoter containing IGF-BP3 box B sequences. Failure to activate transcription was also reflected in the reduced ability of the mutants to bind the p53-responsive DNA sequences present in these promoters. These specific defects in transcriptional activation correlated with the impaired apoptotic function displayed by these mutants, and the results suggest that activation of cell cycle arrest genes by p53 can be separated from activation of genes with a role in mediating the p53 apoptotic response. The cellular response to p53 activation may therefore depend, at least in part, on which group of p53-responsive genes become transcriptionally activated.

scholarly journals The Histone Code of Senescence

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 466 ◽  
Author(s):  
Harikrishnareddy Paluvai ◽  
Eros Di Giorgio ◽  
Claudio Brancolini
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Arrest ◽  
Cellular Response ◽  
Premature Aging ◽  
Physiological Processes ◽  
Cycle Arrest ◽  
Damage Response ◽  
Permanent Cell ◽  
Second Wave

Senescence is the end point of a complex cellular response that proceeds through a set of highly regulated steps. Initially, the permanent cell-cycle arrest that characterizes senescence is a pro-survival response to irreparable DNA damage. The maintenance of this prolonged condition requires the adaptation of the cells to an unfavorable, demanding and stressful microenvironment. This adaptation is orchestrated through a deep epigenetic resetting. A first wave of epigenetic changes builds a dam on irreparable DNA damage and sustains the pro-survival response and the cell-cycle arrest. Later on, a second wave of epigenetic modifications allows the genomic reorganization to sustain the transcription of pro-inflammatory genes. The balanced epigenetic dynamism of senescent cells influences physiological processes, such as differentiation, embryogenesis and aging, while its alteration leads to cancer, neurodegeneration and premature aging. Here we provide an overview of the most relevant histone modifications, which characterize senescence, aging and the activation of a prolonged DNA damage response.

scholarly journals The role of FOXO3 in DNA damage response in thyrocytes

2011 ◽  
Vol 18 (5) ◽  
pp. 555-564 ◽  
Author(s):  
Antje Klagge ◽  
Carl Weidinger ◽  
Kerstin Krause ◽  
Beate Jessnitzer ◽  
Monika Gutknecht ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Arrest ◽  
Cellular Response ◽  
Wild Type ◽  
Cycle Arrest ◽  
Damage Repair ◽  
Cell Clones ◽  
Human Wild Type

Members of the forkhead box-O (FOXO) transcription factors family play an important role in stress defence. FOXO3 deregulation has recently been identified as a hallmark of thyroid carcinogenesis. In this study, we explore the role of FOXO3 in defence of oxidative stress in normal thyrocytes. Stable rat thyroid cell lines were generated expressing either the human wild-type FOXO3, a constitutively activating FOXO3 mutant, or the empty control vector. Cell clones were characterised for proliferation, function and morphology. Hydrogen peroxide and UV irradiation were used to induce oxidative stress. Changes in FOXO3 activity, induction of cell cycle arrest or apoptosis and kinetics of DNA damage repair were analysed. Upregulation of FOXO3 in thyrocytes resulted in decreased proliferation and changes in morphology, but did not affect differentiation. Hydrogen peroxide stimulated the expression of the FOXO3 target genes growth arrest and DNA damage-inducible protein 45 α (Gadd45α) and Bcl-2 interacting mediator of cell death (BIM) and induced programmed cell death in cells with overexpression of the human wild-type FOXO3. In contrast, UV irradiation resulted in a distinct cellular response with activation of FOXO3-c-Jun-N-terminal kinase-Gadd45α signalling and induction of cell cycle arrest at the G2-M-checkpoint. This was accompanied by FOXO3-induced DNA damage repair as evidenced by lower DNA breaks over time in a comet assay in FOXO3 cell clones compared with control cells. In conclusion, FOXO3 is a pivotal relay in the coordination of the cellular response to genotoxic stress in the thyroid. Depending on the stimulus, FOXO3 induces either cell cycle arrest or apoptosis. Conversely, FOXO3 inactivation in thyroid cancers is consistent with genomic instability and loss of cell cycle control.

scholarly journals DNA Damage-induced Heterogeneous Nuclear Ribonucleoprotein K SUMOylation Regulates p53 Transcriptional Activation

2012 ◽  
Vol 287 (36) ◽  
pp. 30789-30799 ◽  
Author(s):  
Federico Pelisch ◽  
Berta Pozzi ◽  
Guillermo Risso ◽  
Manuel Javier Muñoz ◽  
Anabella Srebrow
Keyword(s):  
Dna Damage ◽  
Transcriptional Activation ◽  
Heterogeneous Nuclear Ribonucleoprotein ◽  
Nuclear Ribonucleoprotein

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 Rev7/MAD2B Links c-Jun N-Terminal Protein Kinase Pathway Signaling to Activation of the Transcription Factor Elk-1

2007 ◽  
Vol 27 (8) ◽  
pp. 2861-2869 ◽  
Author(s):  
Lin Zhang ◽  
Shen-Hsi Yang ◽  
Andrew D. Sharrocks
Keyword(s):  
Gene Expression ◽  
Dna Damage ◽  
Transcription Factor ◽  
Protein Kinase ◽  
Transcriptional Activation ◽  
Cellular Response ◽  
Map Kinases ◽  
Target Genes ◽  
Expression Profiles ◽  
Terminal Protein

ABSTRACT The mitogen-activated protein (MAP) kinases represent one of the most important classes of signaling cascades that are used by eukaryotic cells to sense extracellular signals. One of the major responses to these cascades is a change in cellular gene expression profiles mediated through the direct targeting of transcriptional regulators, such as the transcription factor Elk-1. Here we have identified human Rev7 (hRev7)/MAD2B/MAD2L2 as an interaction partner for Elk-1 and demonstrate that hRev7 acts to promote Elk-1 phosphorylation by the c-Jun N-terminal protein kinase (JNK) MAP kinases. As phosphorylation of Elk-1 potentiates the activity of its transcriptional activation domain, hRev7 therefore contributes to the upregulation of Elk-1 target genes, such as egr-1, following exposure of cells to stress conditions caused by DNA-damaging agents. Thus, given its previous roles in permitting DNA damage bypass during replication and regulating cell cycle progression, our data linking hRev7 to gene expression changes suggest that hRev7 has a widespread role in coordinating the cellular response to DNA damage.

scholarly journals DNA Damage Caused by Ionizing Radiation in Embryonic Diploid Fibroblasts WI-38 Induces Both Apoptosis and Senescence

2011 ◽  
pp. 667-677 ◽  
Author(s):  
J. CMIELOVÁ ◽  
R. HAVELEK ◽  
A. JIROUTOVÁ ◽  
R. KOHLEROVÁ ◽  
M. SEIFRTOVÁ ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Ionizing Radiation ◽  
Cellular Response ◽  
Diploid Fibroblasts ◽  
Cycle Arrest ◽  
Permanent Cell ◽  
Radiation Induced ◽  
G2 Phase ◽  
Stress Induced Premature Senescence

Cellular response to ionizing radiation-induced damage depends on the cell type and the ability to repair DNA damage. Some types of cells undergo apoptosis, whereas others induce a permanent cell cycle arrest and do not proliferate. Our study demonstrates two types of response of embryonic diploid fibroblasts WI-38 to ionizing radiation. In the WI-38 cells p53 is activated, protein p21 increases, but the cells are arrested in G2 phase of cell cycle. Some of the cells die by apoptosis, but in remaining viable cells p16 increases, senescence associated DNA-damage foci occur, and senescence-associated beta-galactosidase activity increases, which indicate stress-induced premature senescence.

scholarly journals DNA Damage and Repair Mechanisms Triggered by Exposure to Bioflavonoids and Natural Compounds

2021 ◽  
Author(s):  
Donna Goodenow ◽  
Kiran Lalwani ◽  
Christine Richardson
Keyword(s):  
Dna Damage ◽  
Cellular Response ◽  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
End Joining ◽  
Strand Breaks ◽  
Environmental Agents ◽  
Repair Mechanisms ◽  
Alternative End Joining ◽  
Differentiation Status

Eukaryotic cells use homologous recombination (HR), classical end-joining (C-NHEJ), and alternative end-joining (Alt-EJ) to repair DNA double-strand breaks (DSBs). Repair pathway choice is controlled by the activation and activity of pathways specific proteins in eukaryotes. Activity may be regulated by cell cycle stage, tissue type, and differentiation status. Bioflavonoids and other environmental agents such as pesticides have been shown to biochemically act as inhibitors of topoisomerase II (Top2). In cells, bioflavonoids directly lead to DNA double-strand breaks through both Top2-dependent and independent mechanisms, as well as induce DNA damage response (DDR) signaling, and promote alternative end-joining and chromosome alterations. This chapter will present differences in expression and activity of proteins in major DNA repair pathways, findings of Top2 inhibition by bioflavonoids and cellular response, discuss how these compounds trigger alternative end-joining, and conclude with implications for genome instability and human disease.

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