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The FEBS Journal Jul 2023The central nervous system is particularly susceptible to DNA repair deficiency, which renders a variety of neurodevelopmental and neurodegenerative disorders in humans.... (Review)
Review
The central nervous system is particularly susceptible to DNA repair deficiency, which renders a variety of neurodevelopmental and neurodegenerative disorders in humans. It is generally believed that DNA damage occurs upon repetitive replication and oxidative stress in highly proliferating neuroprogenitor cells (NPs), or due to high rates of metabolism and active neuronal activity in terminally differentiated neurons. DNA double-stranded breaks (DSBs) and single-stranded breaks (SSBs) constitute the most prevalent forms of DNA damage, which can result in neuronal apoptosis if unrepaired. Despite these notions, there are still gaps in our knowledge regarding the mechanism and specificity of DNA damage and repair in the neural development and the homeostasis of neural tissues. Recent studies have identified recurrent DSBs within neuronal long genes in NPs and 'programmed' SSBs in neuronal activity genes. However, the physiological function of these DNA breakages in the nervous system has not been so far explored. In this review, we summarise the recent advances in the field of DNA damage and DNA repair in neural development and neuropathies.
Topics: Humans; DNA Repair; DNA Breaks, Double-Stranded; Neurons; DNA Damage; DNA
PubMed: 35612788
DOI: 10.1111/febs.16535 -
Oral Oncology Sep 2020Ameloblastoma is a rare human disease of benign neoplasm odontogenic tumor with a lower prevalence but higher recurrence rate. Etiology of ameloblastoma is not fully... (Review)
Review
Ameloblastoma is a rare human disease of benign neoplasm odontogenic tumor with a lower prevalence but higher recurrence rate. Etiology of ameloblastoma is not fully understood thus lacks implementation of curative treatments. One of the proposed models of evolution of ameloblastoma is related to alteration in DNA damage and repair effects. Growing body of literature has associated defect in DNA damage and repair mechanisms with cancer risk and various adverse health outcomes in humans. Persistent defect of repair and escape of these genomic unstable cells from cell death mechanisms can contribute towards accumulation of oncogene driver or tumor suppressor mutations selective for malignant transformations. In addition, growth, progression and survival of tumor depends upon its DNA repair mechanisms too, thus identifying a DNA repair biomarker can be of advantageous to eliminate the tumor. Understanding the interconnection of oral lesion and role of various DNA repair mechanisms in context to ameloblastoma will assist to build up a platform for translational based research. This study is a literature review of research work published up to date in the field of ameloblastoma in regard to DNA damage and repair effects.
Topics: Ameloblastoma; DNA Damage; Humans
PubMed: 32474390
DOI: 10.1016/j.oraloncology.2020.104804 -
International Journal of Molecular... Feb 2023Nitrosamines occur widespread in food, drinking water, cosmetics, as well as tobacco smoke and can arise endogenously. More recently, nitrosamines have been detected as... (Review)
Review
Nitrosamines occur widespread in food, drinking water, cosmetics, as well as tobacco smoke and can arise endogenously. More recently, nitrosamines have been detected as impurities in various drugs. This is of particular concern as nitrosamines are alkylating agents that are genotoxic and carcinogenic. We first summarize the current knowledge on the different sources and chemical nature of alkylating agents with a focus on relevant nitrosamines. Subsequently, we present the major DNA alkylation adducts induced by nitrosamines upon their metabolic activation by CYP450 monooxygenases. We then describe the DNA repair pathways engaged by the various DNA alkylation adducts, which include base excision repair, direct damage reversal by MGMT and ALKBH, as well as nucleotide excision repair. Their roles in the protection against the genotoxic and carcinogenic effects of nitrosamines are highlighted. Finally, we address DNA translesion synthesis as a DNA damage tolerance mechanism relevant to DNA alkylation adducts.
Topics: Nitrosamines; DNA Damage; Alkylation; DNA Repair; Alkylating Agents; DNA Adducts
PubMed: 36902118
DOI: 10.3390/ijms24054684 -
Human Genetics Mar 2020DNA damage is one of the most consistent cellular process proposed to contribute to aging. The maintenance of genomic and epigenomic integrity is critical for proper... (Review)
Review
DNA damage is one of the most consistent cellular process proposed to contribute to aging. The maintenance of genomic and epigenomic integrity is critical for proper function of cells and tissues throughout life, and this homeostasis is under constant strain from both extrinsic and intrinsic insults. Considering the relationship between lifespan and genotoxic burden, it is plausible that the longest-lived cellular populations would face an accumulation of DNA damage over time. Tissue-specific stem cells are multipotent populations residing in localized niches and are responsible for maintaining all lineages of their resident tissue/system throughout life. However, many of these stem cells are impacted by genotoxic stress. Several factors may dictate the specific stem cell population response to DNA damage, including the niche location, life history, and fate decisions after damage accrual. This leads to differential handling of DNA damage in different stem cell compartments. Given the importance of adult stem cells in preserving normal tissue function during an individual's lifetime, DNA damage sensitivity and accumulation in these compartments could have crucial implications for aging. Despite this, more support for direct functional effects driven by accumulated DNA damage in adult stem cell compartments is needed. This review will present current evidence for the accumulation and potential influence of DNA damage in adult tissue-specific stem cells and propose inquiry directions that could benefit individual healthspan.
Topics: Aging; Animals; DNA Damage; Homeostasis; Humans; Stem Cells
PubMed: 31324975
DOI: 10.1007/s00439-019-02047-z -
Drug Testing and Analysis Oct 2023The use of electronic cigarettes (e-cigarettes) has increased rapidly in the United States, especially among high school students. e-Cigarettes contain some recognized... (Review)
Review
The use of electronic cigarettes (e-cigarettes) has increased rapidly in the United States, especially among high school students. e-Cigarettes contain some recognized carcinogens and may induce DNA damage in oral cells. The aim of this review is to summarize studies reporting DNA adducts or other types of DNA damage in oral cells in vitro or in vivo upon exposure to e-cigarette vapor and to evaluate the possible connections between e-cigarette exposure and oral cancer. Three databases including PubMed, Scopus, and EMBASE and gray literature were searched for articles published up to April 24, 2022. After screening 321 articles, we extracted 27 for further investigation. Based on the inclusion criteria, 22 articles were eligible for this review. The in vitro studies demonstrate that e-cigarette liquid or vapor can induce DNA damage, oxidative stress, DNA double-stranded breaks, apoptosis, cytotoxicity, and genotoxicity in different types of oral cells. The clinical studies showed that e-cigarette users have significantly higher levels of N'-nitrosonornicotine, acrolein DNA adducts, metanuclear anomalies, gene regulation, and lactate dehydrogenase enzyme expression and significantly lower levels of apurinic/apyrimidinic sites than non-users. Comparison of micronuclei levels between e-cigarette users and non-users gave inconsistent results. e-Cigarettes are implicated in DNA damage to oral cells, but publications to date present limited evidence. Future studies with larger sample sizes are required to investigate the long-term consequences of e-cigarette use.
Topics: Humans; United States; Electronic Nicotine Delivery Systems; DNA Adducts; Tobacco Products; DNA Damage
PubMed: 36169810
DOI: 10.1002/dta.3375 -
Molecules (Basel, Switzerland) May 2020Epigenetic research has rapidly evolved into a dynamic field of genome biology. Chromatin regulation has been proved to be an essential aspect for all genomic processes,... (Review)
Review
Epigenetic research has rapidly evolved into a dynamic field of genome biology. Chromatin regulation has been proved to be an essential aspect for all genomic processes, including DNA repair. Chromatin structure is modified by enzymes and factors that deposit, erase, and interact with epigenetic marks such as DNA and histone modifications, as well as by complexes that remodel nucleosomes. In this review we discuss recent advances on how the chromatin state is modulated during this multi-step process of damage recognition, signaling, and repair. Moreover, we examine how chromatin is regulated when different pathways of DNA repair are utilized. Furthermore, we review additional modes of regulation of DNA repair, such as through the role of global and localized chromatin states in maintaining expression of DNA repair genes, as well as through the activity of epigenetic enzymes on non-nucleosome substrates. Finally, we discuss current and future applications of the mechanistic interplays between chromatin regulation and DNA repair in the context cancer treatment.
Topics: Chromatin Assembly and Disassembly; DNA Damage; DNA Repair; Epigenesis, Genetic; Humans
PubMed: 32471288
DOI: 10.3390/molecules25112496 -
Cold Spring Harbor Perspectives in... Jul 2013Under favorable conditions DNA can survive for thousands of years in the remains of dead organisms. The DNA extracted from such remains is invariably degraded to a small... (Review)
Review
Under favorable conditions DNA can survive for thousands of years in the remains of dead organisms. The DNA extracted from such remains is invariably degraded to a small average size by processes that at least partly involve depurination. It also contains large amounts of deaminated cytosine residues that are accumulated toward the ends of the molecules, as well as several other lesions that are less well characterized.
Topics: DNA; DNA Damage; DNA Fragmentation; Deamination; Sequence Analysis, DNA; Time Factors
PubMed: 23729639
DOI: 10.1101/cshperspect.a012567 -
Current Genetics Feb 2020DNA damage occurs abundantly during normal cellular proliferation. This necessitates that cellular DNA damage response and checkpoint pathways monitor the cellular DNA... (Review)
Review
DNA damage occurs abundantly during normal cellular proliferation. This necessitates that cellular DNA damage response and checkpoint pathways monitor the cellular DNA damage load and that DNA damage signaling is quantitative. Yet, how DNA lesions are counted and converted into a quantitative response remains poorly understood. We have recently obtained insights into this question investigating DNA damage signaling elicited by single-stranded DNA (ssDNA). Intriguingly, our findings suggest that local and global DNA damage signaling react differentially to increasing amounts of DNA damage. In this mini-review, we will discuss these findings and put them into perspective of current knowledge on the DNA damage response.
Topics: DNA Breaks, Double-Stranded; DNA Damage; Gene Expression Regulation; Genomic Instability; Humans; Protein Binding; Signal Transduction
PubMed: 31227863
DOI: 10.1007/s00294-019-01007-4 -
Nature Reviews. Immunology Apr 2019DNA damage occurs on exposure to genotoxic agents and during physiological DNA transactions. DNA double-strand breaks (DSBs) are particularly dangerous lesions that... (Review)
Review
DNA damage occurs on exposure to genotoxic agents and during physiological DNA transactions. DNA double-strand breaks (DSBs) are particularly dangerous lesions that activate DNA damage response (DDR) kinases, leading to initiation of a canonical DDR (cDDR). This response includes activation of cell cycle checkpoints and engagement of pathways that repair the DNA DSBs to maintain genomic integrity. In adaptive immune cells, programmed DNA DSBs are generated at precise genomic locations during the assembly and diversification of lymphocyte antigen receptor genes. In innate immune cells, the production of genotoxic agents, such as reactive nitrogen molecules, in response to pathogens can also cause genomic DNA DSBs. These DSBs in adaptive and innate immune cells activate the cDDR. However, recent studies have demonstrated that they also activate non-canonical DDRs (ncDDRs) that regulate cell type-specific processes that are important for innate and adaptive immune responses. Here, we review these ncDDRs and discuss how they integrate with other signals during immune system development and function.
Topics: Adaptive Immunity; Animals; Cell Cycle Checkpoints; DNA; DNA Breaks, Double-Stranded; DNA Damage; Humans; Immunity, Innate
PubMed: 30778174
DOI: 10.1038/s41577-019-0135-6 -
Environmental and Molecular Mutagenesis Aug 2020Environmental DNA damaging agents continuously challenge the integrity of the genome by introducing a variety of DNA lesions. The DNA damage caused by environmental... (Review)
Review
Environmental DNA damaging agents continuously challenge the integrity of the genome by introducing a variety of DNA lesions. The DNA damage caused by environmental factors will lead to mutagenesis and subsequent carcinogenesis if they are not removed efficiently by repair pathways. Methods for detection of DNA damage and repair can be applied to identify, visualize, and quantify the DNA damage formation and repair events, and they enable us to illustrate the molecular mechanisms of DNA damage formation, DNA repair pathways, mutagenesis, and carcinogenesis. Ever since the discovery of the double helical structure of DNA in 1953, a great number of methods have been developed to detect various types of DNA damage and repair. Rapid advances in sequencing technologies have facilitated the emergence of a variety of novel methods for detecting environmentally induced DNA damage and repair at the genome-wide scale during the last decade. In this review, we provide a historical overview of the development of various damage detection methods. We also highlight the current methodologies to detect DNA damage and repair, especially some next generation sequencing-based methods.
Topics: Animals; Carcinogenesis; DNA; DNA Damage; DNA Repair; Environmental Exposure; High-Throughput Nucleotide Sequencing; Humans; Mutagenesis
PubMed: 32083352
DOI: 10.1002/em.22365