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Current Opinion in Biotechnology Feb 2019Detection and characterization of DNA damage is essential for evaluating genotoxicity, monitoring DNA repair, developing biomarkers for exposures, and evaluating the... (Review)
Review
Detection and characterization of DNA damage is essential for evaluating genotoxicity, monitoring DNA repair, developing biomarkers for exposures, and evaluating the efficacy of chemotherapies. These diverse applications for DNA damage measurements have spurred the continual development and refinement of methodologies for detecting, characterizing, and quantifying DNA damage from isolated DNA and in cells and tissues. Current damage detection methods cover a wide range of techniques from radiolabeling to mass spectrometry, and use of these techniques varies widely based on expense, expertise, and knowledge of adduct formation. More generalizable, easy-to-use methods for detecting and quantifying DNA damage are needed, and there has been an emergence of fluorescence-based methodologies to address this need. Developments in these fluorescence-based strategies are reviewed here.
Topics: Biomarkers; DNA Adducts; DNA Damage; DNA Repair; Enzyme Assays; Fluorescence; Humans
PubMed: 30114673
DOI: 10.1016/j.copbio.2018.08.001 -
Journal of Applied Genetics Aug 2017Investigations on the impact of chemicals on the environment and human health have led to the development of an exposome concept. The exposome refers to the totality of... (Review)
Review
Investigations on the impact of chemicals on the environment and human health have led to the development of an exposome concept. The exposome refers to the totality of exposures received by a person during life, including exposures to life-style factors, from the prenatal period to death. The exposure to genotoxic chemicals and their reactive metabolites can induce chemical modifications of DNA, such as, for example, DNA adducts, which have been extensively studied and which play a key role in chemically induced carcinogenesis. Development of different methods for the identification of DNA adducts has led to adopting DNA adductomic approaches. The ability to simultaneously detect multiple PAH-derived DNA adducts may allow for the improved assessment of exposure, and offer a mechanistic insight into the carcinogenic process following exposure to PAH mixtures. The major advantage of measuring chemical-specific DNA adducts is the assessment of a biologically effective dose. This review provides information about the occurrence of the polycyclic aromatic hydrocarbons (PAHs) and their influence on human exposure and biological effects, including PAH-derived DNA adduct formation and repair processes. Selected methods used for determination of DNA adducts have been presented.
Topics: Biotransformation; DNA Adducts; DNA Damage; DNA Repair; Environmental Exposure; Humans; Polycyclic Aromatic Hydrocarbons
PubMed: 27943120
DOI: 10.1007/s13353-016-0380-3 -
DNA Repair Apr 2022The cellular response to alkylation damage is complex, involving multiple DNA repair pathways and checkpoint proteins, depending on the DNA lesion, the cell type, and... (Review)
Review
The cellular response to alkylation damage is complex, involving multiple DNA repair pathways and checkpoint proteins, depending on the DNA lesion, the cell type, and the cellular proliferation state. The repair of and response to O-alkylation damage, primarily O-methylguaine DNA adducts (O-mG), is the purview of O-methylguanine-DNA methyltransferase (MGMT). Alternatively, this lesion, if left un-repaired, induces replication-dependent formation of the O-mG:T mis-pair and recognition of this mis-pair by the post-replication mismatch DNA repair pathway (MMR). Two models have been suggested to account for MMR and O-mG DNA lesion dependent formation of DNA double-strand breaks (DSBs) and the resulting cytotoxicity - futile cycling and direct DNA damage signaling. While there have been hints at crosstalk between the MMR and base excision repair (BER) pathways, clear mechanistic evidence for such pathway coordination in the formation of DSBs has remained elusive. However, using a novel protein capture approach, Fuchs and colleagues have demonstrated that DSBs result from an encounter between MMR-induced gaps initiated at alkylation induced O-mG:C sites and BER-induced nicks at nearby N-alkylation adducts in the opposite strand. The accidental encounter between these two repair events is causal in the formation of DSBs and the resulting cellular response, documenting a third model to account for O-mG induced cell death in non-replicating cells. This graphical review highlights the details of this Repair Accident model, as compared to current models, and we discuss potential strategies to improve clinical use of alkylating agents such as temozolomide, that can be inferred from the Repair Accident model.
Topics: DNA; DNA Breaks, Double-Stranded; DNA Damage; DNA Repair; O(6)-Methylguanine-DNA Methyltransferase
PubMed: 35219626
DOI: 10.1016/j.dnarep.2022.103303 -
Mutation Research. Reviews in Mutation... 2019CCCTC-binding factor (CTCF) is a highly conserved, ubiquitously expressed zinc finger protein. CTCF is a multifunctional protein, associated with a number of vital... (Review)
Review
CCCTC-binding factor (CTCF) is a highly conserved, ubiquitously expressed zinc finger protein. CTCF is a multifunctional protein, associated with a number of vital cellular processes such as transcriptional activation, repression, insulation, imprinting and genome organization. Emerging evidence indicates that CTCF is also involved in DNA damage response. In this review, we focus on the newly identified role of CTCF in facilitating DNA double-strand break repair. Due to the large number of cellular processes in which CTCF is involved, factors that functionally affect CTCF could have serious implications on genomic stability. It is becoming increasingly clear that exposure to environmental toxicants could have adverse effects on CTCF functions. Here we discuss the various ways that environmental toxicants could impact CTCF functions and the potential consequences on DNA damage response.
Topics: Animals; CCCTC-Binding Factor; DNA Breaks, Double-Stranded; DNA Damage; DNA Repair; Genome; Genomic Instability; Humans
PubMed: 31395350
DOI: 10.1016/j.mrrev.2018.02.002 -
The Journal of Biological Chemistry Jun 2023For cells, it is important to repair DNA damage, such as double-strand and single-strand DNA breaks, because unrepaired DNA can compromise genetic integrity, potentially... (Review)
Review
For cells, it is important to repair DNA damage, such as double-strand and single-strand DNA breaks, because unrepaired DNA can compromise genetic integrity, potentially leading to cell death or cancer. Cells have multiple DNA damage repair pathways that have been the subject of detailed genetic, biochemical, and structural studies. Recently, the scientific community has started to gain evidence that the repair of DNA double-strand breaks may occur within biomolecular condensates and that condensates may also contribute to DNA damage through concentrating genotoxic agents used to treat various cancers. Here, we summarize key features of biomolecular condensates and note where they have been implicated in the repair of DNA double-strand breaks. We also describe evidence suggesting that condensates may be involved in the repair of other types of DNA damage, including single-strand DNA breaks, nucleotide modifications (e.g., mismatch and oxidized bases), and bulky lesions, among others. Finally, we discuss old and new mysteries that could now be addressed considering the properties of condensates, including chemoresistance mechanisms.
Topics: DNA; DNA Breaks, Double-Stranded; DNA Repair; Drug Resistance, Neoplasm; DNA Breaks, Single-Stranded; Base Pair Mismatch
PubMed: 37164156
DOI: 10.1016/j.jbc.2023.104800 -
Scientific Reports Apr 2022To combat the various DNA lesions and their harmful effects, cells have evolved different strategies, collectively referred as DNA damage response (DDR). The DDR largely...
To combat the various DNA lesions and their harmful effects, cells have evolved different strategies, collectively referred as DNA damage response (DDR). The DDR largely relies on intranuclear protein networks, which sense DNA lesions, recruit DNA repair enzymes, and coordinates several aspects of the cellular response, including a temporary cell cycle arrest. In addition, external cues mediated by the surface EGF receptor (EGFR) through downstream signaling pathways contribute to the cellular DNA repair capacity. However, cell cycle progression driven by EGFR activation should be reconciled with cell cycle arrest necessary for effective DNA repair. Here, we show that in damaged cells, the expression of Mig-6 (mitogen-inducible gene 6), a known regulator of EGFR signaling, is reduced resulting in heightened EGFR phosphorylation and downstream signaling. These changes in Mig-6 expression and EGFR signaling do not occur in cells deficient of Mre-11, a component of the MRN complex, playing a central role in double-strand break (DSB) repair or when cells are treated with the MRN inhibitor, mirin. RNAseq and functional analysis reveal that DNA damage induces a shift in cell response to EGFR triggering that potentiates DDR-induced p53 pathway and cell cycle arrest. These data demonstrate that the cellular response to EGFR triggering is skewed by components of the DDR, thus providing a plausible explanation for the paradox of the known role played by a growth factor such as EGFR in the DNA damage repair.
Topics: DNA; DNA Breaks, Double-Stranded; DNA Damage; DNA Repair; ErbB Receptors
PubMed: 35388101
DOI: 10.1038/s41598-022-09779-5 -
Acta Biochimica Et Biophysica Sinica May 2022DNA damage repair and innate immunity are two conserved mechanisms that both function in cellular stress responses. Recently, an increasing amount of evidence has... (Review)
Review
DNA damage repair and innate immunity are two conserved mechanisms that both function in cellular stress responses. Recently, an increasing amount of evidence has uncovered the close relationship between these two ancient biological processes. Here, we review the classical function of factors involved in DNA repair, and especially double-strand break repair, in innate immunity; more importantly, we discuss the novel roles of DNA repair factors in regulating innate immunity and . In addition, we also review the roles of DNA repair, innate immunity and their crosstalk in human diseases, which suggest that these two pathways may be compelling targets for disease prevention and treatment.
Topics: DNA; DNA Breaks, Double-Stranded; DNA Damage; DNA Repair; Humans; Nucleic Acids
PubMed: 35975605
DOI: 10.3724/abbs.2022061 -
Journal of Cancer Research and... 2014Bystander effects (BSEs) have been investigated for a long time but without much deliberation as to the cause in targeted cells and the subsequent effect in naïve... (Review)
Review
Bystander effects (BSEs) have been investigated for a long time but without much deliberation as to the cause in targeted cells and the subsequent effect in naïve cells. BSEs have traditionally been associated with radiation. Currently, this phenomenon is at a juncture where nuclear DNA damage is being debated as either essential or nonessential. If DNA damage is essential for the bystander signal (BSS) production then, this raises a number of questions about, radiotherapy and chemotherapy of cancer patients. This review presents a detailed analysis of the work done to investigate nuclear DNA damage versus exclusively cytoplasmic targeting with ionizing radiations and measurement of bystander end-points in naïve cells. The review also analyzes some of the research work done to investigate cell models that were developed specifically to study and track radiation-induced DNA damage to construct mutation spectra. Production of reactive oxygen species and reactive nitrogen species as possible candidates of the elusive BSS are also discussed besides the signal transduction pathways implicated in reception of a BSS by the naïve cell.
Topics: Animals; Bystander Effect; DNA Damage; Humans; Oxidative Stress; Radiation, Ionizing
PubMed: 25579514
DOI: 10.4103/0973-1482.144587 -
Mutation Research. Reviews in Mutation... 2021The purpose of this review is to evaluate the literature on the genotoxicity of cumene (CAS # 98-82-8) and to assess the role of mutagenicity, if any, in the mode of... (Review)
Review
The purpose of this review is to evaluate the literature on the genotoxicity of cumene (CAS # 98-82-8) and to assess the role of mutagenicity, if any, in the mode of action for cumene-induced rodent tumors. The studies reviewed included microbial mutagenicity, DNA damage/ repair, cytogenetic effects, and gene mutations. In reviewing these studies, attention was paid to their conformance to applicable OECD test guidelines which are considered as internationally recognized standards for performing these assays. Cumene was not a bacterial mutagen and did not induce Hprt mutations in CHO cell cultures. In the primary rat hepatocyte cultures, cumene induced unscheduled DNA synthesis in one study but this response could not be reproduced in an independent study using a similar protocol. In a study that is not fully compliant to the current OECD guideline, no increase in chromosomal aberrations was observed in CHO cells treated with cumene. The weight of the evidence (WoE) from multiple in vivo studies indicates that cumene is not a clastogen or aneugen. The weak positive response in an in vivo comet assay in the rat liver and mouse lung tissues is of questionable significance due to several study deficiencies. The genotoxicity profile of cumene does not match that of a classic DNA-reactive molecule and the available data does not support a conclusion that cumene is an in vivo mutagen. As such, mutagenicity does not appear to be an early key event in cumene-induced rodent tumors and alternate hypothesized non-mutagenic modes-of-action are presented. Further data are necessary to rule in or rule out a particular MoA.
Topics: Animals; CHO Cells; Comet Assay; Cricetulus; DNA Damage; Humans; Mutagenesis; Mutagenicity Tests; Mutation; Rats
PubMed: 34083043
DOI: 10.1016/j.mrrev.2021.108364 -
Advances in Protein Chemistry and... 2019Previously, DNA damage sensing, repairing and signaling machineries were thought to mainly suppress genomic instability in response to genotoxic stress. Emerging... (Review)
Review
Previously, DNA damage sensing, repairing and signaling machineries were thought to mainly suppress genomic instability in response to genotoxic stress. Emerging evidence indicates a crosstalk between DNA repair machinery and the immune system. In this chapter, we attempt to decipher the molecular choreography of how factors, including ATM, BRCA1, DNA-PK, FANCA/D2, MRE11, MUS81, NBS1, RAD51 and TREX1, of multiple DNA metabolic processes are directly or indirectly involved in suppressing cytosolic DNA sensing pathway-mediated immune signaling. We provide systematic details showing how different DDR factors' roles in modulating immune signaling are not direct, but are rather a consequence of their inherent ability to sense, repair and signal in response to DNA damage. Unexpectedly, most DDR factors negatively impact the immune system; that is, the immune system shows defective signaling if there are defects in DNA repair pathways. Thus, in addition to their known DNA repair and replication functions, DDR factors help prevent erroneous activation of immune signaling. A more precise understanding of the mechanisms by which different DDR factors function in immune signaling can be exploited to redirect the immune system for both preventing and treating autoimmunity, cellular senescence and cancer in humans.
Topics: DNA; DNA Damage; DNA Repair; Humans; Signal Transduction
PubMed: 30798935
DOI: 10.1016/bs.apcsb.2018.11.004