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Antioxidants & Redox Signaling May 2011Stroke is a common cause of death and serious long-term adult disability. Oxidative DNA damage is a severe consequence of oxidative stress associated with ischemic... (Review)
Review
Stroke is a common cause of death and serious long-term adult disability. Oxidative DNA damage is a severe consequence of oxidative stress associated with ischemic stroke. The accumulation of DNA lesions, including oxidative base modifications and strand breaks, triggers cell death in neurons and other vulnerable cell populations in the ischemic brain. DNA repair systems, particularly base excision repair, are endogenous defense mechanisms that combat oxidative DNA damage. The capacity for DNA repair may affect the susceptibility of neurons to ischemic stress and influence the pathological outcome of stroke. This article reviews the accumulated understanding of molecular pathways by which oxidative DNA damage is triggered and repaired in ischemic cells, and the potential impact of these pathways on ischemic neuronal cell death/survival. Genetic or pharmacological strategies that target the signaling molecules in DNA repair responses are promising for potential clinically effective treatment. Further understanding of mechanisms for oxidative DNA damage and its repair processes may lead to new avenues for stroke management.
Topics: Animals; Brain Ischemia; DNA Damage; DNA Repair; Humans; Models, Biological; Signal Transduction
PubMed: 20677909
DOI: 10.1089/ars.2010.3451 -
International Journal of Hematology Sep 2017
Topics: Animals; Ataxia Telangiectasia Mutated Proteins; DNA Damage; DNA Repair; DNA Replication; Genomic Instability; Hematologic Neoplasms; Hematopoietic Stem Cells; Humans
PubMed: 28699030
DOI: 10.1007/s12185-017-2301-6 -
Developmental Dynamics : An Official... Jul 2016In most of the mammalian tissues, homeostasis as well as injury repair depend upon a small number of resident adult stem cells. The decline in tissue/organ function in... (Review)
Review
In most of the mammalian tissues, homeostasis as well as injury repair depend upon a small number of resident adult stem cells. The decline in tissue/organ function in aged organisms has been directly linked with poorly functioning stem cells. Altered function of hematopoietic stem cells (HSCs) is at the center of an aging hematopoietic system, a tissue with high cellular turnover. Poorly engrafting, myeloid-biased HSCs with higher levels of DNA damage accumulation are the hallmark features of an aged hematopoietic system. These cells show a higher proliferation rate than their younger counterparts. It was proposed that quiescence of these cells over long period of time leads to accumulation of DNA damage, eventually resulting in poor function/pathological conditions in hematopoietic system. However, various mouse models with premature aging phenotype also show highly proliferative HSCs. This review examines the evidence that links proliferation of HSCs with aging, which leads to functional changes in the hematopoietic system. Developmental Dynamics 245:739-750, 2016. © 2016 Wiley Periodicals, Inc.
Topics: Animals; Cell Cycle; Cell Proliferation; DNA Damage; Hematopoietic Stem Cells; Humans
PubMed: 26813236
DOI: 10.1002/dvdy.24388 -
Journal of Cell Science Mar 2021The DNA damage response (DDR) is the signaling cascade that recognizes DNA double-strand breaks (DSBs) and promotes their resolution via the DNA repair pathways of...
The DNA damage response (DDR) is the signaling cascade that recognizes DNA double-strand breaks (DSBs) and promotes their resolution via the DNA repair pathways of non-homologous end joining (NHEJ) or homologous recombination (HR). We and others have shown that DDR activation requires DROSHA; however, whether DROSHA exerts its functions by associating with damage sites, what controls its recruitment, and how DROSHA influences DNA repair remains poorly understood. Here, we show that DROSHA associates with DSBs independently of transcription. Neither H2AX, nor ATM or DNA-PK kinase activities are required for recruitment of DROSHA to break sites. Rather, DROSHA interacts with RAD50, and inhibition of the MRN complex by mirin treatment abolishes this interaction. MRN complex inactivation by RAD50 knockdown or mirin treatment prevents DROSHA recruitment to DSBs and, as a consequence, also prevents 53BP1 (also known as TP53BP1) recruitment. During DNA repair, DROSHA inactivation reduces NHEJ and boosts HR frequency. Indeed, DROSHA knockdown also increases the association of downstream HR factors such as RAD51 to DNA ends. Overall, our results demonstrate that DROSHA is recruited at DSBs by the MRN complex and directs DNA repair towards NHEJ.
Topics: DNA Breaks, Double-Stranded; DNA Damage; DNA End-Joining Repair; DNA Repair; Homologous Recombination
PubMed: 33558311
DOI: 10.1242/jcs.249706 -
Proceedings of the National Academy of... Jun 2023Understanding and predicting the outcome of the interaction of light with DNA has a significant impact on the study of DNA repair and radiotherapy. We report on a...
Understanding and predicting the outcome of the interaction of light with DNA has a significant impact on the study of DNA repair and radiotherapy. We report on a combination of femtosecond pulsed laser microirradiation at different wavelengths, quantitative imaging, and numerical modeling that yields a comprehensive picture of photon-mediated and free-electron-mediated DNA damage pathways in live cells. Laser irradiation was performed under highly standardized conditions at four wavelengths between 515 nm and 1,030 nm, enabling to study two-photon photochemical and free-electron-mediated DNA damage in situ. We quantitatively assessed cyclobutane pyrimidine dimer (CPD) and γH2AX-specific immunofluorescence signals to calibrate the damage threshold dose at these wavelengths and performed a comparative analysis of the recruitment of DNA repair factors xeroderma pigmentosum complementation group C (XPC) and Nijmegen breakage syndrome 1 (Nbs1). Our results show that two-photon-induced photochemical CPD generation dominates at 515 nm, while electron-mediated damage dominates at wavelengths ≥620 nm. The recruitment analysis revealed a cross talk between nucleotide excision and homologous recombination DNA repair pathways at 515 nm. Numerical simulations predicted electron densities and electron energy spectra, which govern the yield functions of a variety of direct electron-mediated DNA damage pathways and of indirect damage by OH radicals resulting from laser and electron interactions with water. Combining these data with information on free electron-DNA interactions gained in artificial systems, we provide a conceptual framework for the interpretation of the wavelength dependence of laser-induced DNA damage that may guide the selection of irradiation parameters in studies and applications that require the selective induction of DNA lesions.
Topics: Electrons; DNA Damage; Pyrimidine Dimers; DNA Repair; Lasers
PubMed: 37307476
DOI: 10.1073/pnas.2220132120 -
Fungal Genetics and Biology : FG & B Apr 2002The mechanisms used by fungal cells to repair DNA damage have been subjects of intensive investigation for almost 50 years. As a result, the model yeasts... (Review)
Review
The mechanisms used by fungal cells to repair DNA damage have been subjects of intensive investigation for almost 50 years. As a result, the model yeasts Schizosaccharomyces pombe and Saccharomyces cerevisiae have led the way in yielding critical insights into the nature of the DNA damage response. At the same time, largely through the efforts of Etta Kafer, Hirokazu Inoue, and colleagues, a substantial collection of Aspergillus nidulans and Neurospora crassa DNA repair mutants has been identified and characterized in detail. As the analysis of these mutants continues and increasing amounts of annotated genome sequence become available, it is becoming readily apparent that the DNA damage response of filamentous fungi possesses several features that distinguish it from the model yeasts. These features are emphasized in this review, which describes the genes, regulatory networks, and processes that compose the fungal DNA damage response. Further characterization of this response will likely yield general insights that are applicable to animals and plants. Moreover, it may also become evident that the DNA damage response can be manipulated to control fungal growth.
Topics: Apoptosis; DNA Damage; DNA Repair; DNA, Fungal; Fungi; Genes, cdc; Signal Transduction; Ultraviolet Rays
PubMed: 11929209
DOI: 10.1006/fgbi.2002.1344 -
Cell Research Jun 2017High levels of endogenously generated DNA damage drive oncogenesis, sustain malignant progression and increase therapy resistance. In a paper recently published in Cell...
High levels of endogenously generated DNA damage drive oncogenesis, sustain malignant progression and increase therapy resistance. In a paper recently published in Cell Research, Liu and colleagues added additional insights into this topic by uncovering a novel intrinsic source of double-strand breaks that fosters the aggressiveness and stemness of malignant cells.
Topics: DNA; DNA Breaks, Double-Stranded; DNA Damage; DNA Repair
PubMed: 28361897
DOI: 10.1038/cr.2017.43 -
TheScientificWorldJournal Nov 2001The cellular response to DNA damage is vital for the cell"s ability to maintain genomic integrity. Checkpoint signalling pathways, which induce a cell cycle arrest in... (Review)
Review
The cellular response to DNA damage is vital for the cell"s ability to maintain genomic integrity. Checkpoint signalling pathways, which induce a cell cycle arrest in response to DNA damage, are an essential component of this process. This is reflected by the functional conservation of these pathways in all eukaryotes from yeast to mammalian cells. This review will examine the cellular response to DNA damage throughout the cell cycle. A key component of the DNA damage response is checkpoint signalling, which monitors the state of the genome prior to DNA replication (G1/S) and chromosome segregation (G2/M). Checkpoint signalling in model systems including mice, Xenopus laevis, Drosophila melanogaster, and the yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe have been useful in elucidating these pathways in mammalian cells. An examination of this research, with emphasis on the function of checkpoint proteins, their relationship to DNA repair, and their involvement in oncogenesis is undertaken here.
Topics: Animals; Cell Cycle; Cell Transformation, Neoplastic; DNA Damage; DNA Repair; Genes, cdc; Genomic Instability; Humans; Signal Transduction
PubMed: 12805771
DOI: 10.1100/tsw.2001.297 -
Oncogene Dec 1998Ataxia-telangiectasia (AT) is a complex, autosomal recessive disorder characterized by cerebellar ataxia, believed to result from progressive neurodegeneration, and... (Review)
Review
Ataxia-telangiectasia (AT) is a complex, autosomal recessive disorder characterized by cerebellar ataxia, believed to result from progressive neurodegeneration, and telangiectasia, dilation of blood vessels within the eyes and parts of the facial region. AT patients suffer from recurrent infections caused by both cellular and humoral immune deficiencies and as a population, are significantly predisposed to cancer, particularly lymphomas and leukemias. Early attempts at treating these malignancies with radiotherapy revealed another hallmark of AT, a profound hypersensitivity to the cytotoxic effects of ionizing radiation (IR) which is recapitulated at the cellular level in culture. Predisposition to cancer and radiosensitivity observed in AT has been linked to chromosomal instability, abnormalities in genetic recombination, and defective signaling to programmed cell death and several cell cycle checkpoints activated by DNA damage. These earlier observations predicted that the gene defective in AT may encode a protein which plays a crucial role in sensing DNA damage and transducing signals that promote cell survival. Through the combined efforts of linkage analysis and positional cloning, a single gene was identified on chromosome 11q22-33 by Shiloh and colleagues and was found to be mutated in all four complementation groups previously characterized in cell lines derived from AT patients (Savitsky et al., 1995a,b). The predicted ATM gene product shows considerable homology to an emerging family of high molecular weight, phosphatidylinositol-3 kinase (PI-3 K)-related proteins involved in eukaryotic cell cycle control, DNA repair, and DNA recombination (Zakian, 1995). This landmark discovery has triggered a resurgence of biochemical and genetic studies focusing on ATM function which has brought forth insights regarding ATM activity and its role in DNA damage signaling.
Topics: Animals; Ataxia Telangiectasia; Ataxia Telangiectasia Mutated Proteins; Cell Cycle Proteins; DNA Damage; DNA-Binding Proteins; Genetic Predisposition to Disease; Humans; Neoplasms; Protein Serine-Threonine Kinases; Proteins; Signal Transduction; Tumor Suppressor Proteins
PubMed: 9916992
DOI: 10.1038/sj.onc.1202577 -
Seminars in Cancer Biology Jun 2016
Topics: DNA Damage; DNA Repair; Humans
PubMed: 27113557
DOI: 10.1016/j.semcancer.2016.04.001