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Neurobiology of Disease Jan 2021Traumatic brain injury (TBI) is known to promote significant DNA damage irrespective of age, sex, and species. Chemical as well as structural DNA modification start... (Review)
Review
Traumatic brain injury (TBI) is known to promote significant DNA damage irrespective of age, sex, and species. Chemical as well as structural DNA modification start within minutes and persist for days after TBI. Although several DNA repair pathways are induced following TBI, the simultaneous downregulation of some of the genes and proteins of these pathways leads to an aberrant overall DNA repair process. In many instances, DNA damages escape even the most robust repair mechanisms, especially when the repair process becomes overwhelmed or becomes inefficient by severe or repeated injuries. The persisting DNA damage and/or lack of DNA repair contributes to long-term functional deficits. In this review, we discuss the mechanisms of TBI-induced DNA damage and repair. We further discussed the putative experimental therapies that target the members of the DNA repair process for improved outcome following TBI.
Topics: Animals; Brain Injuries, Traumatic; DNA Damage; DNA Repair; Humans
PubMed: 33127471
DOI: 10.1016/j.nbd.2020.105143 -
Genes & Development Dec 2019Diverse linkage in polyubiquitin chain structure gives cells an unparalleled complexity to virtually modulate all aspects of cell biology. Substrates can be covalently... (Review)
Review
Diverse linkage in polyubiquitin chain structure gives cells an unparalleled complexity to virtually modulate all aspects of cell biology. Substrates can be covalently modified by ubiquitin chains of different topology. Proper DNA damage response takes advantage of this regulatory system and heavily relies on ubiquitin-based signaling. Moreover, increasing evidence suggests that chain specificity dictates DNA repair outcome. In this issue of , Wu and colleagues (pp. 1702-1717) show that Cezanne and Cezanne2, two paralogous deubiquitinating enzymes that are recruited to sites of DNA damage, ensure proper local polyubiquitin chain composition for downstream DNA repair protein assembly. Their study offers a key insight into the mechanism of crosstalk between linkage-specific ubiquitylation at DNA damage sites, while simultaneously raising important questions for future research.
Topics: DNA Damage; DNA Repair; Polyubiquitin; Protein Binding; Ubiquitin; Ubiquitination
PubMed: 31792015
DOI: 10.1101/gad.334383.119 -
Experimental Hematology Mar 2020Clonal hematopoiesis is a common premalignant condition defined by the abnormal expansion of clonally derived hematopoietic stem cells carrying somatic mutations in... (Review)
Review
Clonal hematopoiesis is a common premalignant condition defined by the abnormal expansion of clonally derived hematopoietic stem cells carrying somatic mutations in leukemia-associated genes. Apart from increasing age, this phenomenon occurs with higher frequency in individuals with lymphoid or solid tumors and is associated with exposures to genotoxic stress. Clonal hematopoiesis in this context confers a greater risk for developing therapy-related myeloid neoplasms and appears to contribute to adverse cancer-related survival through a variety of potential mechanisms. These include alterations of the bone marrow microenvironment, inflammatory changes in clonal effector cells and modulation of immune responses. Understanding how clonal hematopoiesis drives therapy-related myeloid neoplasm initiation and interactions with non-myeloid malignancies will inform screening and surveillance approaches and suggest targeted therapies in this vulnerable population. Here, we examine the clinical implications of clonal hematopoiesis in the cancer setting and discuss potential strategies to mitigate the adverse consequences of clonal expansion.
Topics: Clonal Evolution; DNA Damage; Hematologic Neoplasms; Hematopoiesis; Humans; Myeloproliferative Disorders
PubMed: 32044376
DOI: 10.1016/j.exphem.2020.02.001 -
Annual Review of Genetics Nov 2023Transcription and replication both require large macromolecular complexes to act on a DNA template, yet these machineries cannot simultaneously act on the same DNA... (Review)
Review
Transcription and replication both require large macromolecular complexes to act on a DNA template, yet these machineries cannot simultaneously act on the same DNA sequence. Conflicts between the replication and transcription machineries (transcription-replication conflicts, or TRCs) are widespread in both prokaryotes and eukaryotes and have the capacity to both cause DNA damage and compromise complete, faithful replication of the genome. This review will highlight recent studies investigating the genomic locations of TRCs and the mechanisms by which they may be prevented, mitigated, or resolved. We address work from both model organisms and mammalian systems but predominantly focus on multicellular eukaryotes owing to the additional complexities inherent in the coordination of replication and transcription in the context of cell type-specific gene expression and higher-order chromatin organization.
Topics: Animals; Transcription, Genetic; DNA Replication; Genomic Instability; Eukaryota; DNA Damage; Mammals
PubMed: 37552891
DOI: 10.1146/annurev-genet-080320-031523 -
Reviews on Environmental Health Mar 2023Inappropriate processing and disposal of electronic waste (e-waste) expose workers and surrounding populations to hazardous chemicals, including clastogens and aneugens.... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
Inappropriate processing and disposal of electronic waste (e-waste) expose workers and surrounding populations to hazardous chemicals, including clastogens and aneugens. Recently, considerable literature has grown around e-waste recycling, associated chemical exposures and intermediate health outcomes, including DNA damage. Micronuclei (MN) frequency has been widely used as a biomarker to investigate DNA damage in human populations exposed to genotoxic agents. We conducted a systematic review of published studies to assess DNA damage in e-waste-exposed populations and performed a meta-analysis to evaluate the association between e-waste exposure and DNA damage.
METHODS
This systematic review with meta-analysis was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement checklist. Articles published in English from January 2000 through December 2020 investigating the associations between e-waste exposure and DNA damage were retrieved from the following three major databases: MEDLINE, ProQuest, and Scopus. Studies that reported the use of MN assay as a biomarker of DNA damage were included for meta-analysis. Studies that also reported other DNA damage biomarkers such as chromosomal aberrations, comet assay biomarkers, 8-hydroxy-2'-deoxyguanosine (8-OHdG), telomere length, apoptosis rate were reported using narrative synthesis.
RESULTS
A total of 20 publications were included in this review, of which seven studies were within the occupational setting, and the remaining 13 studies were ecological studies. The review found six biomarkers of DNA damage (micronuclei, comets assay parameters (tail length, % tail DNA, tail moment, and olive tail moment), 8-OHdG, telomere length, apoptosis rate and chromosomal aberrations) which were assessed using seven different biological matrices (buccal cells, blood, umbilical cord blood, placenta, urine and semen). Most studies showed elevated levels of DNA damage biomarkers among e-waste exposed populations than in control populations. The most commonly used biomarkers were micronuclei frequency (n=9) in peripheral blood lymphocytes or buccal cells and 8-OHdG (n=7) in urine. The results of the meta-analysis showed that electronic waste recycling has contributed to an increased risk of DNA damage measured using MN frequency with a pooled estimate of the standardized mean difference (SMD) of 2.30 (95% CI: 1.36, 3.24, p<0.001) based on 865 participants.
CONCLUSIONS
Taken together, evidence from this systematic review with meta-analysis suggest that occupational and non-occupational exposure to e-waste processing is associated with increased risk of DNA damage measured through MN assay and other types of DNA damage biomarkers. However, more studies from other developing countries in Africa, Latin America, and South Asia are needed to confirm and increase these results' generalizability.
Topics: Humans; Electronic Waste; Mouth Mucosa; DNA Damage; Chromosome Aberrations; Biomarkers
PubMed: 34727591
DOI: 10.1515/reveh-2021-0074 -
Translational Neurodegeneration Apr 2023Redox homeostasis refers to the balance between the production of reactive oxygen species (ROS) as well as reactive nitrogen species (RNS), and their elimination by... (Review)
Review
Redox homeostasis refers to the balance between the production of reactive oxygen species (ROS) as well as reactive nitrogen species (RNS), and their elimination by antioxidants. It is linked to all important cellular activities and oxidative stress is a result of imbalance between pro-oxidants and antioxidant species. Oxidative stress perturbs many cellular activities, including processes that maintain the integrity of DNA. Nucleic acids are highly reactive and therefore particularly susceptible to damage. The DNA damage response detects and repairs these DNA lesions. Efficient DNA repair processes are therefore essential for maintaining cellular viability, but they decline considerably during aging. DNA damage and deficiencies in DNA repair are increasingly described in age-related neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and Huntington's disease. Furthermore, oxidative stress has long been associated with these conditions. Moreover, both redox dysregulation and DNA damage increase significantly during aging, which is the biggest risk factor for neurodegenerative diseases. However, the links between redox dysfunction and DNA damage, and their joint contributions to pathophysiology in these conditions, are only just emerging. This review will discuss these associations and address the increasing evidence for redox dysregulation as an important and major source of DNA damage in neurodegenerative disorders. Understanding these connections may facilitate a better understanding of disease mechanisms, and ultimately lead to the design of better therapeutic strategies based on preventing both redox dysregulation and DNA damage.
Topics: Humans; Neurodegenerative Diseases; Oxidative Stress; Oxidation-Reduction; Reactive Oxygen Species; Antioxidants; DNA Damage
PubMed: 37055865
DOI: 10.1186/s40035-023-00350-4 -
Cell Death & Disease Nov 2023DNA double-strand breaks (DSBs) are the fatal type of DNA damage mostly induced by exposure genome to ionizing radiation or genotoxic chemicals. DSBs are mainly repaired... (Review)
Review
DNA double-strand breaks (DSBs) are the fatal type of DNA damage mostly induced by exposure genome to ionizing radiation or genotoxic chemicals. DSBs are mainly repaired by homologous recombination (HR) and nonhomologous end joining (NHEJ). To repair DSBs, a large amount of DNA repair factors was observed to be concentrated at the end of DSBs in a specific spatiotemporal manner to form a repair center. Recently, this repair center was characterized as a condensate derived from liquid-liquid phase separation (LLPS) of key DSBs repair factors. LLPS has been found to be the mechanism of membraneless organelles formation and plays key roles in a variety of biological processes. In this review, the recent advances and mechanisms of LLPS in the formation of DSBs repair-related condensates are summarized.
Topics: DNA Breaks, Double-Stranded; DNA Repair; DNA End-Joining Repair; DNA Damage; DNA
PubMed: 37968256
DOI: 10.1038/s41419-023-06267-0 -
DNA Repair Aug 2023DNA adducts and strand breaks are induced by various exogenous and endogenous agents. Accumulation of DNA damage is implicated in many disease processes, including... (Review)
Review
DNA adducts and strand breaks are induced by various exogenous and endogenous agents. Accumulation of DNA damage is implicated in many disease processes, including cancer, aging, and neurodegeneration. The continuous acquisition of DNA damage from exogenous and endogenous stressors coupled with defects in DNA repair pathways contribute to the accumulation of DNA damage within the genome and genomic instability. While mutational burden offers some insight into the level of DNA damage a cell may have experienced and subsequently repaired, it does not quantify DNA adducts and strand breaks. Mutational burden also infers the identity of the DNA damage. With advances in DNA adduct detection and quantification methods, there is an opportunity to identify DNA adducts driving mutagenesis and correlate with a known exposome. However, most DNA adduct detection methods require isolation or separation of the DNA and its adducts from the context of the nuclei. Mass spectrometry, comet assays, and other techniques precisely quantify lesion types but lose the nuclear context and even tissue context of the DNA damage. The growth in spatial analysis technologies offers a novel opportunity to leverage DNA damage detection with nuclear and tissue context. However, we lack a wealth of techniques capable of detecting DNA damage in situ. Here, we review the limited existing in situ DNA damage detection methods and examine their potential to offer spatial analysis of DNA adducts in tumors or other tissues. We also offer a perspective on the need for spatial analysis of DNA damage in situ and highlight Repair Assisted Damage Detection (RADD) as an in situ DNA adduct technique with the potential to integrate with spatial analysis and the challenges to be addressed.
Topics: Humans; DNA Adducts; DNA Damage; DNA Repair; Mutagenesis; Neoplasms
PubMed: 37390674
DOI: 10.1016/j.dnarep.2023.103529 -
Trends in Genetics : TIG Dec 2023Genome integrity and maintenance are essential for the viability of all organisms. A wide variety of DNA damage types have been described, but double-strand breaks... (Review)
Review
Genome integrity and maintenance are essential for the viability of all organisms. A wide variety of DNA damage types have been described, but double-strand breaks (DSBs) stand out as one of the most toxic DNA lesions. Two major pathways account for the repair of DSBs: homologous recombination (HR) and non-homologous end joining (NHEJ). Both pathways involve complex DNA transactions catalyzed by proteins that sequentially or cooperatively work to repair the damage. Single-molecule methods allow visualization of these complex transactions and characterization of the protein:DNA intermediates of DNA repair, ultimately allowing a comprehensive breakdown of the mechanisms underlying each pathway. We review current understanding of the HR and NHEJ responses to DSBs in eukaryotic cells, with a particular emphasis on recent advances through the use of single-molecule techniques.
Topics: DNA Breaks, Double-Stranded; DNA Repair; DNA; DNA Damage; DNA End-Joining Repair
PubMed: 37806853
DOI: 10.1016/j.tig.2023.09.004 -
Trends in Biochemical Sciences Jan 2024DNA single-strand breaks (SSBs) are among the most common lesions arising in human cells, with tens to hundreds of thousands arising in each cell, each day. Cells have... (Review)
Review
DNA single-strand breaks (SSBs) are among the most common lesions arising in human cells, with tens to hundreds of thousands arising in each cell, each day. Cells have efficient mechanisms for the sensing and repair of these ubiquitous DNA lesions, but the failure of these processes to rapidly remove SSBs can lead to a variety of pathogenic outcomes. The threat posed by unrepaired SSBs is illustrated by the existence of at least six genetic diseases in which SSB repair (SSBR) is defective, all of which are characterised by neurodevelopmental and/or neurodegenerative pathology. Here, I review current understanding of how SSBs arise and impact on critical molecular processes, such as DNA replication and gene transcription, and their links to human disease.
Topics: Humans; DNA Repair; DNA Breaks, Single-Stranded; DNA Damage; DNA Replication; DNA
PubMed: 38040599
DOI: 10.1016/j.tibs.2023.11.001