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Uchu Seibutsu Kagaku Dec 2004Clustered DNA damage (locally multiply damaged site) is thought to be a critical lesion caused by ionizing radiation, and high LET radiation such as heavy ion particles... (Review)
Review
Clustered DNA damage (locally multiply damaged site) is thought to be a critical lesion caused by ionizing radiation, and high LET radiation such as heavy ion particles is believed to produce high yields of such damage. Since heavy ion particles are major components of ionizing radiation in a space environment, it is important to clarify the chemical nature and biological consequences of clustered DNA damage and its relationship to the health effects of exposure to high LET particles in humans. The concept of clustered DNA damage emerged around 1980, but only recently has become the subject of experimental studies. In this article, we review methods used to detect clustered DNA damage, and the current status of our understanding of the chemical nature and repair of clustered DNA damage.
Topics: Cosmic Radiation; DNA Damage; DNA Glycosylases; DNA Repair; Electrophoresis, Gel, Pulsed-Field; Endonucleases; Heavy Ions; Humans; Hydroxyl Radical; Linear Energy Transfer; Radiation Dosage; Radiation, Ionizing
PubMed: 15858387
DOI: 10.2187/bss.18.206 -
Molecular Cell Dec 2007The DNA damage response (DDR), through the action of sensors, transducers, and effectors, orchestrates the appropriate repair of DNA damage and resolution of DNA... (Review)
Review
The DNA damage response (DDR), through the action of sensors, transducers, and effectors, orchestrates the appropriate repair of DNA damage and resolution of DNA replication problems, coordinating these processes with ongoing cellular physiology. In the past decade, we have witnessed an explosion in understanding of DNA damage sensing, signaling, and the complex interplay between protein phosphorylation and the ubiquitin pathway employed by the DDR network to execute the response to DNA damage. These findings have important implications for aging and cancer.
Topics: Animals; DNA Damage; DNA Repair; Humans; Proteasome Endopeptidase Complex; Protein Processing, Post-Translational; Ubiquitin; Ubiquitin-Protein Ligase Complexes
PubMed: 18082599
DOI: 10.1016/j.molcel.2007.11.015 -
Free Radical Research Apr 2012Endogenous and exogenous sources cause free radical-induced DNA damage in living organisms by a variety of mechanisms. The highly reactive hydroxyl radical reacts with... (Review)
Review
Endogenous and exogenous sources cause free radical-induced DNA damage in living organisms by a variety of mechanisms. The highly reactive hydroxyl radical reacts with the heterocyclic DNA bases and the sugar moiety near or at diffusion-controlled rates. Hydrated electron and H atom also add to the heterocyclic bases. These reactions lead to adduct radicals, further reactions of which yield numerous products. These include DNA base and sugar products, single- and double-strand breaks, 8,5'-cyclopurine-2'-deoxynucleosides, tandem lesions, clustered sites and DNA-protein cross-links. Reaction conditions and the presence or absence of oxygen profoundly affect the types and yields of the products. There is mounting evidence for an important role of free radical-induced DNA damage in the etiology of numerous diseases including cancer. Further understanding of mechanisms of free radical-induced DNA damage, and cellular repair and biological consequences of DNA damage products will be of outmost importance for disease prevention and treatment.
Topics: Animals; DNA; DNA Damage; Free Radicals; Humans; Oxidative Stress
PubMed: 22276778
DOI: 10.3109/10715762.2011.653969 -
Impaired DNA damage response--an Achilles' heel sensitizing cancer to chemotherapy and radiotherapy.European Journal of Pharmacology Dec 2009Despite the progress in targeting particular molecular abnormalities specific to different cancers (targeted therapy), chemo- and radiotherapies are still the most... (Review)
Review
Despite the progress in targeting particular molecular abnormalities specific to different cancers (targeted therapy), chemo- and radiotherapies are still the most effective of all anticancer modalities. Induction of DNA damage and inhibition of cell proliferation are the objects of most chemotherapeutic agents and radiation. Their effectiveness was initially thought to be due to the high rate of proliferation of cancer cells. However, normal cell proliferation rate in some tissues often exceeds that of curable tumors. Most tumors have impaired DNA damage response (DDR) and the evidence is forthcoming that this confers sensitivity to chemo- or radiotherapy. DDR is a complex set of events which elicits a plethora of molecular interactions engaging signaling pathways designed to: (a) halt cell cycle progression and division to prevent transfer of DNA damage to progeny cells; (b) increase the accessibility of the damaged sites to the DNA repair machinery; (c) engage DNA repair mechanisms and (d) activate the apoptotic pathway when DNA cannot be successfully repaired. A defective DDR makes cancer cells unable to effectively stop cell cycle progression, engage in DNA repair and/or trigger the apoptotic program when treated with DNA damaging drugs. With continued exposure to the drug, such cells accumulate DNA damage which leads to their reproductive death that may have features of cell senescence. Cancers with nonfunctional BRCA1 and BRCA2 are particularly sensitive to combined treatment with DNA damaging drugs and inhibitors of poly(ADP-ribose) polymerase. Antitumor strategies are being designed to treat cancers having particular defects in their DDR, concurrent with protecting normal cells.
Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Proliferation; DNA Damage; DNA Repair; Drug Delivery Systems; Drug Design; Humans; Neoplasms
PubMed: 19836377
DOI: 10.1016/j.ejphar.2009.05.032 -
Cell Cycle (Georgetown, Tex.) 2015
Topics: Animals; DNA Damage; Humans; Longevity; Models, Biological; Signal Transduction
PubMed: 25591056
DOI: 10.1080/15384101.2015.1006543 -
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 -
Discovery Medicine Oct 2012For more than 200 years human cancer induction has been known to be associated with a large variety of chemical exposures. Most exposures to chemical carcinogens occur... (Review)
Review
For more than 200 years human cancer induction has been known to be associated with a large variety of chemical exposures. Most exposures to chemical carcinogens occur as a result of occupation, pollution in the ambient environment, lifestyle choices, or pharmaceutical use. Scientific investigations have revealed that the majority of cancer causing chemicals, or chemical carcinogens, act through "genotoxic" or DNA damaging mechanisms, which involve covalent binding of the chemical to DNA (DNA adduct formation). Cancer-inducing exposures are typically frequent and/or chronic over years, and the accumulation of DNA damage or DNA adduct formation is considered to be a necessary requirement for tumor induction. Studies in animal models have indicated that the ability to reduce DNA damage will also result in reduction of tumor risk, leading to the hypothesis that individuals having the highest levels of DNA adducts may have an increased cancer risk, compared to individuals with the lowest levels of DNA adducts. Here we have reviewed twelve investigations showing 2- to 9-fold increased Relative Risks (RR) or Odds Ratios (OR) for cancer in (the 25% of) individuals having the highest DNA adduct levels, compared to (the 25% of) matched individuals with the lowest DNA adducts. These studies also provided preliminary evidence that multiple types of DNA adducts combined, or DNA adducts combined with other risk factors (such as infection or inflammation), may be associated with more than 10-fold higher cancer risks (RR = 34-60), compared to those found with a single carcinogen. Taken together the data suggest that a reduction in human DNA adduct level is likely to produce a reduction in human cancer risk.
Topics: Aflatoxins; Carcinogens; DNA Damage; Humans; Neoplasms; Risk Factors
PubMed: 23114584
DOI: No ID Found -
Cell Biology and Toxicology Oct 2018Maintenance of genome integrity is essential for all organisms because genome information regulates cell proliferation, growth arrest, and vital metabolic processes in... (Review)
Review
Maintenance of genome integrity is essential for all organisms because genome information regulates cell proliferation, growth arrest, and vital metabolic processes in cells, tissues, organs, and organisms. Because genomes are constantly exposed to intrinsic and extrinsic genotoxic stress, cellular DNA repair machinery and proper DNA damage responses (DDR) have evolved to quickly eliminate genotoxic DNA lesions, thus maintaining the genome integrity suitably. In human, germline mutations in genes involved not only in cellular DNA repair pathways but also in cellular DDR machinery frequently predispose hereditary diseases associated with chromosome aberrations. These genetic syndromes typically displaying mutations in DNA repair/DDR-related genes are often called "genome instability syndromes." Common features of these hereditary syndromes include a high incidence of cancers and developmental abnormalities including short stature, microcephaly, and/or neurological deficiencies. However, precisely how impaired DNA repair and/or dysfunctional DDR pathologically promote(s) these syndromes are poorly understood. In this review article, we summarize the clinical symptoms of several representatives "genome instability syndromes" and propose the plausible pathogenesis thereof.
Topics: DNA; DNA Breaks, Double-Stranded; DNA Damage; DNA Repair; Disease; Genomic Instability; Humans; Syndrome
PubMed: 29623483
DOI: 10.1007/s10565-018-9429-x -
Molecular Carcinogenesis Sep 2003It has been reported that 80-90% of human cancers may result, in part, from DNA damage. Cell survival depends critically on the stability of our DNA and exquisitely... (Review)
Review
It has been reported that 80-90% of human cancers may result, in part, from DNA damage. Cell survival depends critically on the stability of our DNA and exquisitely sensitive DNA repair mechanisms have developed as a result. In humans, nucleotide excision repair (NER) protects the DNA against the mutagenic effects of carcinogens and ultraviolet (UV) radiation from sun exposure. By preventing mutations from forming in the DNA, the repair machinery ultimately protects us from developing cancers. DNA damage recognition is the rate-limiting step in repair, and although many details of NER have been elucidated, the mechanisms by which DNA damage is recognized remain to be fully determined. Two primary protein complexes have been proposed as the damaged DNA recognition factor in NER: xeroderma pigmentosum protein A-replication protein A (XPA-RPA) and xeroderma pigmentosum protein C-human homolog of RAD23B (XPC-hHR23B). Here we compare the evidence that supports damage detection by these protein complexes and propose a model for DNA damage recognition in NER based on the current understanding of the roles these proteins may play in the processing of DNA lesions.
Topics: DNA; DNA Damage; DNA Repair; DNA-Binding Proteins; Humans
PubMed: 12949838
DOI: 10.1002/mc.10143 -
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