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Molecular Cancer Research : MCR Feb 2020Radiation, alkylating agents, and platinum-based chemotherapy treatments eliminate cancer cells through the induction of excessive DNA damage. The resultant DNA damage... (Review)
Review
Radiation, alkylating agents, and platinum-based chemotherapy treatments eliminate cancer cells through the induction of excessive DNA damage. The resultant DNA damage challenges the cancer cell's DNA repair capacity. Among the different types of DNA damage induced in cells, double-strand breaks (DSB) are the most lethal if left unrepaired. Unrepaired DSBs in tumor cells exacerbate existing gene deletions, chromosome losses and rearrangements, and aberrant features that characteristically enable tumor progression, metastasis, and drug resistance. Tumor microenvironmental factors like hypoxia, inflammation, cellular metabolism, and the immune system profoundly influence DSB repair mechanisms. Here, we put into context the role of the microenvironment in governing DSB repair mechanisms.
Topics: DNA Breaks, Double-Stranded; DNA Damage; Genomics; Humans; Neoplasms; Tumor Microenvironment
PubMed: 31676722
DOI: 10.1158/1541-7786.MCR-19-0665 -
Molecular Human Reproduction Jan 2010DNA damage in the male germ line has been linked with a variety of adverse clinical outcomes including impaired fertility, an increased incidence of miscarriage and an... (Review)
Review
DNA damage in the male germ line has been linked with a variety of adverse clinical outcomes including impaired fertility, an increased incidence of miscarriage and an enhanced risk of disease in the offspring. The origins of this DNA damage could, in principle, involve: (i) abortive apoptosis initiated post meiotically when the ability to drive this process to completion is in decline (ii) unresolved strand breaks created during spermiogenesis to relieve the torsional stresses associated with chromatin remodelling and (iii) oxidative stress. In this article, we present a two-step hypothesis for the origins of DNA damage in human spermatozoa that highlights the significance of oxidative stress acting on vulnerable, poorly protaminated cells generated as a result of defective spermiogenesis. We further propose that these defective cells are characterized by several hallmarks of 'dysmaturity' including the retention of excess residual cytoplasm, persistent nuclear histones, poor zona binding and disrupted chaperone content. The oxidative stress experienced by these cells may originate from infiltrating leukocytes or, possibly, the entry of spermatozoa into an apoptosis-like cascade characterized by the mitochondrial generation of reactive oxygen species. This oxidative stress may be exacerbated by a decline in local antioxidant protection, particularly during epididymal maturation. Finally, if oxidative stress is a major cause of sperm DNA damage then antioxidants should have an important therapeutic role to play in the clinical management of male infertility. Carefully controlled studies are now needed to critically examine this possibility.
Topics: Chromatin; DNA Damage; Humans; Male; Models, Biological; Reactive Oxygen Species; Spermatozoa
PubMed: 19648152
DOI: 10.1093/molehr/gap059 -
Oncogene Aug 2013The consequences of DNA damage depend on the cell type and the severity of the damage. Mild DNA damage can be repaired with or without cell-cycle arrest. More severe and... (Review)
Review
The consequences of DNA damage depend on the cell type and the severity of the damage. Mild DNA damage can be repaired with or without cell-cycle arrest. More severe and irreparable DNA injury leads to the appearance of cells that carry mutations or causes a shift towards induction of the senescence or cell death programs. Although for many years it was argued that DNA damage kills cells via apoptosis or necrosis, technical and methodological progress during the last few years has helped to reveal that this injury might also activate death by autophagy or mitotic catastrophe, which may then be followed by apoptosis or necrosis. The molecular basis underlying the decision-making process is currently the subject of intense investigation. Here, we review current knowledge about the response to DNA damage and subsequent signaling, with particular attention to cell death induction and the molecular switches between different cell death modalities following damage.
Topics: Animals; Cell Death; DNA Damage; Humans
PubMed: 23208502
DOI: 10.1038/onc.2012.556 -
Future Oncology (London, England) Feb 2013The cellular reaction to genomic instability includes a network of signal transduction pathways collectively referred to as the DNA damage response (DDR). Activated by a... (Review)
Review
The cellular reaction to genomic instability includes a network of signal transduction pathways collectively referred to as the DNA damage response (DDR). Activated by a variety of DNA lesions, the DDR orchestrates cell cycle arrest and DNA repair, and initiates apoptosis in instances where damage cannot be repaired. As such, disruption of the DDR increases the prevalence of DNA damage secondary to incomplete repair, and in doing so, enhances radiation-induced cytotoxicity. This article describes the molecular agents and their targets within DDR pathways that sensitize cells to radiation. Moreover, it reviews the therapeutic implications of these compounds, provides an overview of relevant clinical trials and offers a viewpoint on the evolution of the field in the years to come.
Topics: Animals; DNA Damage; Humans; Radiation Tolerance; Radiation-Sensitizing Agents; Signal Transduction
PubMed: 23414472
DOI: 10.2217/fon.12.185 -
Mutation Research Mar 1999Malondialdehyde is a naturally occurring product of lipid peroxidation and prostaglandin biosynthesis that is mutagenic and carcinogenic. It reacts with DNA to form... (Review)
Review
Malondialdehyde is a naturally occurring product of lipid peroxidation and prostaglandin biosynthesis that is mutagenic and carcinogenic. It reacts with DNA to form adducts to deoxyguanosine and deoxyadenosine. The major adduct to DNA is a pyrimidopurinone called M1G. Site-specific mutagenesis experiments indicate that M1G is mutagenic in bacteria and is repaired by the nucleotide excision repair pathway. M1G has been detected in liver, white blood cells, pancreas, and breast from healthy human beings at levels ranging from 1-120 per 108 nucleotides. Several different assays for M1G have been described that are based on mass spectrometry, 32P-postlabeling, or immunochemical techniques. Each technique offers advantages and disadvantages based on a combination of sensitivity and specificity. Application of each of these techniques to the analysis of M1G is reviewed and future needs for improvements are identified. M1G appears to be a major endogenous DNA adduct in human beings that may contribute significantly to cancer linked to lifestyle and dietary factors. High throughput methods for its detection and quantitation will be extremely useful for screening large populations.
Topics: Animals; DNA Adducts; DNA Damage; Humans; Lipid Peroxidation; Malondialdehyde; Mutagenesis, Site-Directed
PubMed: 10064852
DOI: 10.1016/s0027-5107(99)00010-x -
Proceedings of the National Academy of... Mar 2022SignificanceDNA damage causes loss of or alterations in genetic information, resulting in cell death or mutations. Ionizing radiations produce local, multiple DNA damage...
SignificanceDNA damage causes loss of or alterations in genetic information, resulting in cell death or mutations. Ionizing radiations produce local, multiple DNA damage sites called clustered DNA damage. In this study, a complete protocol was established to analyze the damage complexity of clustered DNA damage, wherein damage-containing genomic DNA fragments were selectively concentrated via pulldown, and clustered DNA damage was visualized by atomic force microscopy. It was found that X-rays and Fe ion beams caused clustered DNA damage. Fe ion beams also produced clustered DNA damage with high complexity. Fe ion beam-induced complex DNA double-strand breaks (DSBs) containing one or more base lesion(s) near the DSB end were refractory to repair, implying their lethal effects.
Topics: DNA; DNA Breaks, Double-Stranded; DNA Damage; DNA Repair; Microscopy, Atomic Force; Radiation, Ionizing
PubMed: 35324325
DOI: 10.1073/pnas.2119132119 -
Current Opinion in Genetics &... Feb 2000DNA damage or stalled DNA replication can activate specific signal transduction pathways, termed checkpoints. Checkpoint activation can result in increased repair,... (Review)
Review
DNA damage or stalled DNA replication can activate specific signal transduction pathways, termed checkpoints. Checkpoint activation can result in increased repair, induction of a transcriptional programme and inhibition of cell-cycle progression. Recent results have suggested possible mechanisms for the detection of specific DNA structures, provided further information on the organisation of the signal transduction cascade and demonstrated involvement of the checkpoint pathway in DNA repair.
Topics: Animals; Apoptosis; Cell Cycle; DNA Damage; DNA Repair; Genes, cdc; Humans; Signal Transduction; Yeasts
PubMed: 10679395
DOI: 10.1016/s0959-437x(99)00050-7 -
Mutation Research. Reviews in Mutation... 2021The alkaline comet assay, or single cell gel electrophoresis, is one of the most popular methods for assessing DNA damage in human population. One of the open issues... (Review)
Review
The hCOMET project: International database comparison of results with the comet assay in human biomonitoring. Baseline frequency of DNA damage and effect of main confounders.
The alkaline comet assay, or single cell gel electrophoresis, is one of the most popular methods for assessing DNA damage in human population. One of the open issues concerning this assay is the identification of those factors that can explain the large inter-individual and inter-laboratory variation. International collaborative initiatives such as the hCOMET project - a COST Action launched in 2016 - represent a valuable tool to meet this challenge. The aims of hCOMET were to establish reference values for the level of DNA damage in humans, to investigate the effect of host factors, lifestyle and exposure to genotoxic agents, and to compare different sources of assay variability. A database of 19,320 subjects was generated, pooling data from 105 studies run by 44 laboratories in 26 countries between 1999 and 2019. A mixed random effect log-linear model, in parallel with a classic meta-analysis, was applied to take into account the extensive heterogeneity of data, due to descriptor, specimen and protocol variability. As a result of this analysis interquartile intervals of DNA strand breaks (which includes alkali-labile sites) were reported for tail intensity, tail length, and tail moment (comet assay descriptors). A small variation by age was reported in some datasets, suggesting higher DNA damage in oldest age-classes, while no effect could be shown for sex or smoking habit, although the lack of data on heavy smokers has still to be considered. Finally, highly significant differences in DNA damage were found for most exposures investigated in specific studies. In conclusion, these data, which confirm that DNA damage measured by the comet assay is an excellent biomarker of exposure in several conditions, may contribute to improving the quality of study design and to the standardization of results of the comet assay in human populations.
Topics: Biomarkers; Comet Assay; DNA Damage; Humans
PubMed: 34083035
DOI: 10.1016/j.mrrev.2021.108371 -
Environmental Health Perspectives Dec 1993The temporal relationship between DNA damage and DNA replication may be critical in determining whether the genetic changes necessary for cellular transformation occur... (Review)
Review
The temporal relationship between DNA damage and DNA replication may be critical in determining whether the genetic changes necessary for cellular transformation occur after DNA damage. Recent characterization of the mechanisms responsible for alterations in cell-cycle progression after DNA damage in our laboratory have implicated the p53 (tumor suppressor) protein in the G1 arrest that occurs after certain types of DNA damage. In particular, we found that levels of p53 protein increased rapidly and transiently after nonlethal doses of gamma irradiation (XRT) in hematopoietic cells with wild-type, but not mutant, p53 genes. These changes in p53 protein levels were temporally linked to a transient G1 arrest in these cells. Hematopoietic cells with mutant or absent p53 genes did not exhibit this G1 arrest, through they continued to demonstrate a G2 arrest. We recently extended these observations of a tight correlation between the status of the endogenous p53 genes and this G1 arrest after XRT and this cell-cycle alteration after XRT was then established by transfecting cells lacking endogenous p53 genes with a wild-type gene and observing acquisition of the G1 arrest and by transfecting cells processing endogenous wild-type p53 genes with a mutant p53 gene and observing loss of the G1 arrest after XRT. These observations and their significance for our understanding of the mechanisms of DNA damage-induced cellular transformation are discussed.
Topics: Animals; DNA Damage; DNA Replication; G1 Phase; Gamma Rays; Genes, p53; Humans; Mutation
PubMed: 8013425
DOI: 10.1289/ehp.93101s555 -
Mutation Research Oct 2003Genomes are damaged by spontaneous decay, chemicals, radiation and replication errors. DNA damage may cause mutations resulting in inheritable disease, cancer and... (Review)
Review
Genomes are damaged by spontaneous decay, chemicals, radiation and replication errors. DNA damage may cause mutations resulting in inheritable disease, cancer and ageing. Oxidative stress from ionising radiation and oxidative metabolism causes base damage, as well as strand breaks in DNA. Base damage is mostly indirect and caused by reactive oxygen species (ROS) generated, e.g. O2(.-) (superoxide radical), OH. (hydroxyl radical) and H2O2 (hydrogen peroxide). ROS also oxidise RNA, lipids, proteins and nucleotides. The first line of defence against ROS is enzymatic inactivation of superoxide by superoxide dismutase and inactivation of the less toxic hydrogen peroxide by catalase. As a second line of defence, incorporation of damaged bases into DNA is prevented by enzymes that hydrolyse oxidised dNTPs (e.g. 8-oxodGTP) to the corresponding dNMP. The third line of defence is repair of oxidative damage in DNA by an intricate network of DNA repair mechanisms. Base excision repair (BER), transcription-coupled repair (TCR), global genome repair (GGR), mismatch repair (MMR), translesion synthesis (TLS), homologous recombination (HR) and non-homologous end-joining (NHEJ) all contribute to repair of oxidative DNA damage. These mechanisms are also integrated with other cellular processes such as cell cycle regulation, transcription and replication and even use some common proteins. BER is the major pathway for repair of oxidative base damage, with TCR and MMR being important backup pathways for repair of transcribed strands and newly replicated strands, respectively. In recent years, several new DNA glycosylases that initiate BER of oxidative damage have been identified. These have specificities overlapping with previously known DNA glycosylases and serve as backups, and may have distinct roles as well. Thus, there is both inter- and intra-pathway complementation in repair of oxidative base damage, explaining the limited effects of absence of single DNA glycosylases in animal model systems.
Topics: Base Pair Mismatch; DNA Adducts; DNA Damage; DNA Repair; Mutagenesis; Oxidation-Reduction; Oxidative Stress; Reactive Oxygen Species
PubMed: 14637258
DOI: 10.1016/j.mrfmmm.2003.06.002