Detecting Recruitment of DNA Damage Response Factors Through the eChIP Approach

2011 ◽  
pp. 245-255 ◽  
Author(s):  
Yucai Wang ◽  
Lei Li
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Response Factors ◽  
Damage Response

scholarly journals The Intra- and Extra-Telomeric Role of TRF2 in the DNA Damage Response

2021 ◽  
Vol 22 (18) ◽  
pp. 9900
Author(s):  
Siti A. M. Imran ◽  
Muhammad Dain Yazid ◽  
Wei Cui ◽  
Yogeswaran Lokanathan
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Response Factors ◽  
Telomere Repeat ◽  
Protection Mechanism ◽  
Dna Instability ◽  
Binding Factor ◽  
Damage Response ◽  
Dna Break

Telomere repeat binding factor 2 (TRF2) has a well-known function at the telomeres, which acts to protect the telomere end from being recognized as a DNA break or from unwanted recombination. This protection mechanism prevents DNA instability from mutation and subsequent severe diseases caused by the changes in DNA, such as cancer. Since TRF2 actively inhibits the DNA damage response factors from recognizing the telomere end as a DNA break, many more studies have also shown its interactions outside of the telomeres. However, very little has been discovered on the mechanisms involved in these interactions. This review aims to discuss the known function of TRF2 and its interaction with the DNA damage response (DDR) factors at both telomeric and non-telomeric regions. In this review, we will summarize recent progress and findings on the interactions between TRF2 and DDR factors at telomeres and outside of telomeres.

Quantitative analysis of DNA-damage response factors after sequential ion microirradiation

2008 ◽  
Vol 47 (4) ◽  
pp. 415-422 ◽  
Author(s):  
Christoph Greubel ◽  
Volker Hable ◽  
Guido A. Drexler ◽  
Andreas Hauptner ◽  
Steffen Dietzel ◽  
...  
Keyword(s):  
Dna Damage ◽  
Quantitative Analysis ◽  
Dna Damage Response ◽  
Response Factors ◽  
Damage Response

scholarly journals Topoisomerase-Mediated DNA Damage in Neurological Disorders

2021 ◽  
Vol 13 ◽  
Author(s):  
Morgan Crewe ◽  
Ram Madabhushi
Keyword(s):  
Dna Damage ◽  
Nervous System ◽  
Dna Damage Response ◽  
Neurological Disorders ◽  
Neuronal Dysfunction ◽  
Cellular Mechanisms ◽  
Response Factors ◽  
Damage Response ◽  
Potential Sources ◽  
Repair Mechanisms

The nervous system is vulnerable to genomic instability and mutations in DNA damage response factors lead to numerous developmental and progressive neurological disorders. Despite this, the sources and mechanisms of DNA damage that are most relevant to the development of neuronal dysfunction are poorly understood. The identification of primarily neurological abnormalities in patients with mutations in TDP1 and TDP2 suggest that topoisomerase-mediated DNA damage could be an important underlying source of neuronal dysfunction. Here we review the potential sources of topoisomerase-induced DNA damage in neurons, describe the cellular mechanisms that have evolved to repair such damage, and discuss the importance of these repair mechanisms for preventing neurological disorders.

scholarly journals In Vitro Nephrotoxicity Studies of Established and Experimental Platinum-Based Compounds

Biomedicines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 1033
Author(s):  
Sarah Schoch ◽  
Vasily Sen ◽  
Walburgis Brenner ◽  
Andrea Hartwig ◽  
Beate Köberle
Keyword(s):  
Dna Damage ◽  
Proximal Tubule ◽  
Dna Damage Response ◽  
Transcriptional Response ◽  
Human Kidney ◽  
Epithelial Cell Line ◽  
Response Factors ◽  
Damage Response ◽  
Platinum Accumulation

Cisplatin is one of the most commonly used drugs for the treatment of various solid cancers. However, its efficacy is restricted by severe side effects, especially dose-limiting nephrotoxicity. New platinum-based compounds are designed to overcome this limitation. Previous investigations showed that the platinum(IV)–nitroxyl complex PN149 is highly cytotoxic in various tumor cell lines. In the present study, investigations with PN149 were extended to normal human kidney tubule epithelia. Coincident with higher intracellular platinum accumulation, the cytotoxicity of PN149 in the proximal tubule epithelial cell line ciPTEC was more pronounced compared to the established platinum chemotherapeutics cisplatin, carboplatin and oxaliplatin. Quantitative gene expression profiling revealed the induction of ROS-inducible and anti-oxidative genes, suggesting an oxidative stress response by PN149. However, in contrast to cisplatin, no pro-inflammatory response was observed. Genes coding for distinct DNA damage response factors and genes related to apoptosis were up-regulated, indicating the activation of the DNA damage response system and induction of the apoptotic cascade by PN149. Altogether, a comparable transcriptional response was observed for PN149 and the platinum chemotherapeutics. However, the lack of inflammatory activity, which is a possible cause contributing to toxicity in human renal proximal tubule epithelia, might indicate the reduced nephrotoxic potential of PN149.

scholarly journals Simian Virus Large T Antigen Interacts with the N-Terminal Domain of the 70 kD Subunit of Replication Protein A in the Same Mode as Multiple DNA Damage Response Factors

PLoS ONE ◽  
2015 ◽  
Vol 10 (2) ◽  
pp. e0116093 ◽  
Author(s):  
Boting Ning ◽  
Michael D. Feldkamp ◽  
David Cortez ◽  
Walter J. Chazin ◽  
Katherine L. Friedman ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Protein A ◽  
Replication Protein A ◽  
Simian Virus ◽  
T Antigen ◽  
Replication Protein ◽  
Large T Antigen ◽  
Response Factors ◽  
Damage Response

scholarly journals 53BP1 regulates DNA resection and the choice between classical and alternative end joining during class switch recombination

2010 ◽  
Vol 207 (4) ◽  
pp. 855-865 ◽  
Author(s):  
Anne Bothmer ◽  
Davide F. Robbiani ◽  
Niklas Feldhahn ◽  
Anna Gazumyan ◽  
Andre Nussenzweig ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Cytidine Deaminase ◽  
Class Switch Recombination ◽  
Dna Double Strand Breaks ◽  
End Joining ◽  
Response Factors ◽  
Class Switch ◽  
Damage Response ◽  
Switch Regions

Class switch recombination (CSR) diversifies antibodies by joining highly repetitive DNA elements, which are separated by 60–200 kbp. CSR is initiated by activation-induced cytidine deaminase, an enzyme that produces multiple DNA double-strand breaks (DSBs) in switch regions. Switch regions are joined by a mechanism that requires an intact DNA damage response and classical or alternative nonhomologous end joining (A-NHEJ). Among the DNA damage response factors, 53BP1 has the most profound effect on CSR. We explore the role of 53BP1 in intrachromosomal DNA repair using I-SceI to introduce paired DSBs in the IgH locus. We find that the absence of 53BP1 results in an ataxia telangiectasia mutated–dependent increase in DNA end resection and that resected DNA is preferentially repaired by microhomology-mediated A-NHEJ. We propose that 53BP1 favors long-range CSR in part by protecting DNA ends against resection, which prevents A-NHEJ–dependent short-range rejoining of intra–switch region DSBs.

scholarly journals Phosphorylation-Dependent Regulation of the DNA Damage Response of Adaptor Protein KIBRA in Cancer Cells

2016 ◽  
Vol 36 (9) ◽  
pp. 1354-1365 ◽  
Author(s):  
Jayadev Mavuluri ◽  
Swarnalatha Beesetti ◽  
Rohan Surabhi ◽  
Joachim Kremerskothen ◽  
Ganesh Venkatraman ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Cancer Cells ◽  
Dna Damage Response ◽  
Adaptor Protein ◽  
Adaptor Proteins ◽  
Site Directed Mutagenesis ◽  
Scaffolding Protein ◽  
Response Factors ◽  
Damage Response

Multifunctional adaptor proteins encompassing various protein-protein interaction domains play a central role in the DNA damage response pathway. In this report, we show that KIBRA is a physiologically interacting reversible substrate of ataxia telangiectasia mutated (ATM) kinase. We identified the site of phosphorylation in KIBRA as threonine 1006, which is embedded within the serine/threonine (S/T) Q consensus motif, by site-directed mutagenesis, and we further confirmed the same with a phospho-(S/T) Q motif-specific antibody. Results from DNA repair functional assays such as the γ-H2AX assay, pulsed-field gel electrophoresis (PFGE), Comet assay, terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) assay, and clonogenic cell survival assay using stable overexpression clones of wild-type (wt.) KIBRA and active (T1006E) and inactive (T1006A) KIBRA phosphorylation mutants showed that T1006 phosphorylation on KIBRA is essential for optimal DNA double-strand break repair in cancer cells. Further, results from stable retroviral short hairpin RNA-mediated knockdown (KD) clones of KIBRA and KIBRA knockout (KO) model cells generated by a clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9 system showed that depleting KIBRA levels compromised the DNA repair functions in cancer cells upon inducing DNA damage. All these phenotypic events were reversed upon reconstitution of KIBRA into cells lacking KIBRA knock-in (KI) model cells. All these results point to the fact that phosphorylated KIBRA might be functioning as a scaffolding protein/adaptor protein facilitating the platform for further recruitment of other DNA damage response factors. In summary, these data demonstrate the imperative functional role of KIBRAper se(KIBRA phosphorylation at T1006 site as a molecular switch that regulates the DNA damage response, possibly via the nonhomologous end joining [NHEJ] pathway), suggesting that KIBRA could be a potential therapeutic target for modulating chemoresistance in cancer cells.

scholarly journals Focusing on Foci: H2AX and the Recruitment of DNA-Damage Response Factors

Cell Cycle ◽  
2003 ◽  
Vol 2 (5) ◽  
pp. 425-426 ◽  
Author(s):  
Oscar Fernandez-Capetillo ◽  
Arkady Celeste ◽  
André Nussenzweig
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Response Factors ◽  
Damage Response

scholarly journals Inhibition of HSP90 as a Strategy to Radiosensitize Glioblastoma: Targeting the DNA Damage Response and Beyond

2021 ◽  
Vol 11 ◽  
Author(s):  
Michael Orth ◽  
Valerie Albrecht ◽  
Karin Seidl ◽  
Linda Kinzel ◽  
Kristian Unger ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Treatment Resistance ◽  
Clonogenic Survival ◽  
Hsp90 Inhibition ◽  
Response Factors ◽  
Dismal Prognosis ◽  
Damage Response

Radiotherapy is an essential component of multi-modality treatment of glioblastoma (GBM). However, treatment failure and recurrence are frequent and give rise to the dismal prognosis of this aggressive type of primary brain tumor. A high level of inherent treatment resistance is considered to be the major underlying reason, stemming from constantly activated DNA damage response (DDR) mechanisms as a consequence of oncogene overexpression, persistent replicative stress, and other so far unknown reasons. The molecular chaperone heat shock protein 90 (HSP90) plays an important role in the establishment and maintenance of treatment resistance, since it crucially assists the folding and stabilization of various DDR regulators. Accordingly, inhibition of HSP90 represents a multi-target strategy to interfere with DDR function and to sensitize cancer cells to radiotherapy. Using NW457, a pochoxime-based HSP90 inhibitor with favorable brain pharmacokinetic profile, we show here that HSP90 inhibition at low concentrations with per se limited cytotoxicity leads to downregulation of various DNA damage response factors on the protein level, distinct transcriptomic alterations, impaired DNA damage repair, and reduced clonogenic survival in response to ionizing irradiation in glioblastoma cells in vitro. In vivo, HSP90 inhibition by NW457 improved the therapeutic outcome of fractionated CBCT-based irradiation in an orthotopic, syngeneic GBM mouse model, both in terms of tumor progression and survival. Nevertheless, in view of the promising in vitro results the in vivo efficacy was not as strong as expected, although apart from the radiosensitizing effects HSP90 inhibition also reduced irradiation-induced GBM cell migration and tumor invasiveness. Hence, our findings identify the combination of HSP90 inhibition and radiotherapy in principle as a promising strategy for GBM treatment whose performance needs to be further optimized by improved inhibitor substances, better formulations and/or administration routes, and fine-tuned treatment sequences.

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