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Journal of Visualized Experiments : JoVE Oct 2017DNA damage is a common phenomenon for each cell during its lifespan, and is defined as an alteration of the chemical structure of genomic DNA. Cancer therapies, such as...
DNA damage is a common phenomenon for each cell during its lifespan, and is defined as an alteration of the chemical structure of genomic DNA. Cancer therapies, such as radio- and chemotherapy, introduce enormous amount of additional DNA damage, leading to cell cycle arrest and apoptosis to limit cancer progression. Quantitative assessment of DNA damage during experimental cancer therapy is a key step to justify the effectiveness of a genotoxic agent. In this study, we focus on a single cell electrophoresis assay, also known as the comet assay, which can quantify single and double-strand DNA breaks in vitro. The comet assay is a DNA damage quantification method that is efficient and easy to perform, and has low time/budget demands and high reproducibility. Here, we highlight the utility of the comet assay for a preclinical study by evaluating the genotoxic effect of olaparib/temozolomide combination therapy to U251 glioma cells.
Topics: Comet Assay; DNA Damage; Electrophoresis; Humans; Reproducibility of Results
PubMed: 29053680
DOI: 10.3791/56450 -
Neural Plasticity 2016
Topics: Animals; DNA Damage; Humans; Nerve Degeneration; Neuronal Plasticity
PubMed: 27313899
DOI: 10.1155/2016/1206840 -
Signal Transduction and Targeted Therapy Sep 2023Genome instability has been identified as one of the enabling hallmarks in cancer. DNA damage response (DDR) network is responsible for maintenance of genome integrity... (Review)
Review
Genome instability has been identified as one of the enabling hallmarks in cancer. DNA damage response (DDR) network is responsible for maintenance of genome integrity in cells. As cancer cells frequently carry DDR gene deficiencies or suffer from replicative stress, targeting DDR processes could induce excessive DNA damages (or unrepaired DNA) that eventually lead to cell death. Poly (ADP-ribose) polymerase (PARP) inhibitors have brought impressive benefit to patients with breast cancer gene (BRCA) mutation or homologous recombination deficiency (HRD), which proves the concept of synthetic lethality in cancer treatment. Moreover, the other two scenarios of DDR inhibitor application, replication stress and combination with chemo- or radio- therapy, are under active clinical exploration. In this review, we revisited the progress of DDR targeting therapy beyond the launched first-generation PARP inhibitors. Next generation PARP1 selective inhibitors, which could maintain the efficacy while mitigating side effects, may diversify the application scenarios of PARP inhibitor in clinic. Albeit with unavoidable on-mechanism toxicities, several small molecules targeting DNA damage checkpoints (gatekeepers) have shown great promise in preliminary clinical results, which may warrant further evaluations. In addition, inhibitors for other DNA repair pathways (caretakers) are also under active preclinical or clinical development. With these progresses and efforts, we envision that a new wave of innovations within DDR has come of age.
Topics: Humans; Cell Death; DNA Damage; Drug-Related Side Effects and Adverse Reactions; Genomic Instability
PubMed: 37679326
DOI: 10.1038/s41392-023-01548-8 -
International Journal of Molecular... Jan 2017
Topics: Animals; DNA Damage; DNA Repair; Diet; Disease; Epigenesis, Genetic; Humans; Oxidative Stress
PubMed: 28275213
DOI: 10.3390/ijms18010166 -
International Journal of Molecular... Jun 2018
Topics: Animals; DNA Damage; DNA Repair; DNA Replication; Disease; Genome, Human; Humans; Phosphorylation
PubMed: 29958460
DOI: 10.3390/ijms19071902 -
Biomolecules Dec 2022Developing B and T lymphocytes requires programmed DNA double-strand breaks followed by the activation of the DNA damage response (DDR) pathway and DNA repair [...].
Developing B and T lymphocytes requires programmed DNA double-strand breaks followed by the activation of the DNA damage response (DDR) pathway and DNA repair [...].
Topics: DNA Damage; DNA Repair; DNA Breaks, Double-Stranded; T-Lymphocytes
PubMed: 36671469
DOI: 10.3390/biom13010084 -
Chemical Research in Toxicology Mar 2014Systems toxicology is a broad-based approach to describe many of the toxicological features that occur within a living system under stress or subjected to exogenous or... (Review)
Review
Systems toxicology is a broad-based approach to describe many of the toxicological features that occur within a living system under stress or subjected to exogenous or endogenous exposures. The ultimate goal is to capture an overview of all exposures and the ensuing biological responses of the body. The term exposome has been employed to refer to the totality of all exposures, and systems toxicology investigates how the exposome influences health effects and consequences of exposures over a lifetime. The tools to advance systems toxicology include high-throughput transcriptomics, proteomics, metabolomics, and adductomics, which is still in its infancy. A well-established methodology for the comprehensive measurement of DNA damage resulting from every day exposures is not fully developed. During the past several decades, the (32)P-postlabeling technique has been employed to screen the damage to DNA induced by multiple classes of genotoxicants; however, more robust, specific, and quantitative methods have been sought to identify and quantify DNA adducts. Although triple quadrupole and ion trap mass spectrometry, particularly when using multistage scanning (LC-MS(n)), have shown promise in the field of DNA adductomics, it is anticipated that high-resolution and accurate-mass LC-MS(n) instrumentation will play a major role in assessing global DNA damage. Targeted adductomics should also benefit greatly from improved triple quadrupole technology. Once the analytical MS methods are fully mature, DNA adductomics along with other -omics tools will contribute greatly to the field of systems toxicology.
Topics: Chromatography, High Pressure Liquid; DNA; DNA Adducts; DNA Damage; Mass Spectrometry; Metabolomics; Proteomics; Xenobiotics
PubMed: 24437709
DOI: 10.1021/tx4004352 -
International Journal of Molecular... Jun 2018
Topics: Animals; DNA Damage; DNA Repair; Humans; Mutagenesis; Neoplasms
PubMed: 29899224
DOI: 10.3390/ijms19061767 -
International Journal of Molecular... Apr 2022Neurological complications directly impact the lives of hundreds of millions of people worldwide. While the precise molecular mechanisms that underlie neuronal cell loss... (Review)
Review
Neurological complications directly impact the lives of hundreds of millions of people worldwide. While the precise molecular mechanisms that underlie neuronal cell loss remain under debate, evidence indicates that the accumulation of genomic DNA damage and consequent cellular responses can promote apoptosis and neurodegenerative disease. This idea is supported by the fact that individuals who harbor pathogenic mutations in DNA damage response genes experience profound neuropathological manifestations. The review article here provides a general overview of the nervous system, the threats to DNA stability, and the mechanisms that protect genomic integrity while highlighting the connections of DNA repair defects to neurological disease. The information presented should serve as a prelude to the Special Issue "Genome Stability and Neurological Disease", where experts discuss the role of DNA repair in preserving central nervous system function in greater depth.
Topics: DNA Damage; DNA Repair; Genome; Genomic Instability; Humans; Neurodegenerative Diseases
PubMed: 35456958
DOI: 10.3390/ijms23084142 -
Seminars in Cancer Biology Oct 2022The acquisition of DNA damage is an early driving event in tumorigenesis. Premalignant lesions show activated DNA damage responses and inactivation of DNA damage... (Review)
Review
The acquisition of DNA damage is an early driving event in tumorigenesis. Premalignant lesions show activated DNA damage responses and inactivation of DNA damage checkpoints promotes malignant transformation. However, DNA damage is also a targetable vulnerability in cancer cells. This requires a detailed understanding of the cellular and molecular mechanisms governing DNA integrity. Here, we review current work on DNA damage in tumorigenesis. We discuss DNA double strand break repair, how repair pathways contribute to tumorigenesis, and how double strand breaks are linked to the tumor microenvironment. Next, we discuss the role of oncogenes in promoting DNA damage through replication stress. Finally, we discuss our current understanding on DNA damage in micronuclei and discuss therapies targeting these DNA damage pathways.
Topics: Humans; DNA Repair; DNA Damage; DNA Breaks, Double-Stranded; Cell Transformation, Neoplastic; DNA; Genomic Instability; Tumor Microenvironment
PubMed: 33905873
DOI: 10.1016/j.semcancer.2021.04.012