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International Journal of Molecular... Apr 2022Neurological complications directly impact the lives of hundreds of millions of people worldwide. While the precise molecular mechanisms that underlie neuronal cell loss... (Review)
Review
Neurological complications directly impact the lives of hundreds of millions of people worldwide. While the precise molecular mechanisms that underlie neuronal cell loss remain under debate, evidence indicates that the accumulation of genomic DNA damage and consequent cellular responses can promote apoptosis and neurodegenerative disease. This idea is supported by the fact that individuals who harbor pathogenic mutations in DNA damage response genes experience profound neuropathological manifestations. The review article here provides a general overview of the nervous system, the threats to DNA stability, and the mechanisms that protect genomic integrity while highlighting the connections of DNA repair defects to neurological disease. The information presented should serve as a prelude to the Special Issue "Genome Stability and Neurological Disease", where experts discuss the role of DNA repair in preserving central nervous system function in greater depth.
Topics: DNA Damage; DNA Repair; Genome; Genomic Instability; Humans; Neurodegenerative Diseases
PubMed: 35456958
DOI: 10.3390/ijms23084142 -
Seminars in Cancer Biology Oct 2022The acquisition of DNA damage is an early driving event in tumorigenesis. Premalignant lesions show activated DNA damage responses and inactivation of DNA damage... (Review)
Review
The acquisition of DNA damage is an early driving event in tumorigenesis. Premalignant lesions show activated DNA damage responses and inactivation of DNA damage checkpoints promotes malignant transformation. However, DNA damage is also a targetable vulnerability in cancer cells. This requires a detailed understanding of the cellular and molecular mechanisms governing DNA integrity. Here, we review current work on DNA damage in tumorigenesis. We discuss DNA double strand break repair, how repair pathways contribute to tumorigenesis, and how double strand breaks are linked to the tumor microenvironment. Next, we discuss the role of oncogenes in promoting DNA damage through replication stress. Finally, we discuss our current understanding on DNA damage in micronuclei and discuss therapies targeting these DNA damage pathways.
Topics: Humans; DNA Repair; DNA Damage; DNA Breaks, Double-Stranded; Cell Transformation, Neoplastic; DNA; Genomic Instability; Tumor Microenvironment
PubMed: 33905873
DOI: 10.1016/j.semcancer.2021.04.012 -
Journal of Molecular Cell Biology Mar 2019Inactivation of the p53 gene is a key driver of tumorigenesis in various cancer cohorts and types. The quest for a successful p53-based therapy that holds the promise of... (Review)
Review
Inactivation of the p53 gene is a key driver of tumorigenesis in various cancer cohorts and types. The quest for a successful p53-based therapy that holds the promise of treating more than half of the cancer population has culminated in extensive knowledge about the role and function of p53 and led to new proposed innovative strategies against p53-defective cancers. We will discuss some of these latest studies with a focus on metabolic regulation and DNA damage response and also highlight novel functions of p53 in these pathways that may provide a contemporary rationale for targeting p53 loss in tumors.
Topics: Animals; Cell Transformation, Neoplastic; DNA Damage; Humans; Neoplasms; Tumor Suppressor Protein p53
PubMed: 30865230
DOI: 10.1093/jmcb/mjz012 -
Genes Jun 2023Cells are constantly assaulted by endogenous and exogenous sources of DNA damage that threaten genome stability [...].
Cells are constantly assaulted by endogenous and exogenous sources of DNA damage that threaten genome stability [...].
Topics: Humans; DNA Repair; DNA Damage; Genomic Instability
PubMed: 37510290
DOI: 10.3390/genes14071385 -
DNA Repair Jul 2014The concept of the Exposome is a compilation of diseases and one's lifetime exposure to chemicals, whether the exposure comes from environmental, dietary, or... (Review)
Review
The concept of the Exposome is a compilation of diseases and one's lifetime exposure to chemicals, whether the exposure comes from environmental, dietary, or occupational exposures; or endogenous chemicals that are formed from normal metabolism, inflammation, oxidative stress, lipid peroxidation, infections, and other natural metabolic processes such as alteration of the gut microbiome. In this review, we have focused on the endogenous exposome, the DNA damage that arises from the production of endogenous electrophilic molecules in our cells. It provides quantitative data on endogenous DNA damage and its relationship to mutagenesis, with emphasis on when exogenous chemical exposures that produce identical DNA adducts to those arising from normal metabolism cause significant increases in total identical DNA adducts. We have utilized stable isotope labeled chemical exposures of animals and cells, so that accurate relationships between endogenous and exogenous exposures can be determined. Advances in mass spectrometry have vastly increased both the sensitivity and accuracy of such studies. Furthermore, we have clear evidence of which sources of exposure drive low dose biology that results in mutations and disease. These data provide much needed information to impact quantitative risk assessments, in the hope of moving towards the use of science, rather than default assumptions.
Topics: Animals; Antioxidant Response Elements; DNA Adducts; DNA Damage; Dose-Response Relationship, Drug; Isotope Labeling; Mutagenesis
PubMed: 24767943
DOI: 10.1016/j.dnarep.2014.03.031 -
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 -
International Journal of Molecular... Dec 2017Within the nucleus, sub-nuclear domains define territories where specific functions occur. Nuclear bodies (NBs) are dynamic structures that concentrate nuclear factors... (Review)
Review
Within the nucleus, sub-nuclear domains define territories where specific functions occur. Nuclear bodies (NBs) are dynamic structures that concentrate nuclear factors and that can be observed microscopically. Recently, NBs containing the p53 binding protein 1 (53BP1), a key component of the DNA damage response, were defined. Interestingly, 53BP1 NBs are visualized during G1 phase, in daughter cells, while DNA damage was generated in mother cells and not properly processed. Unlike most NBs involved in transcriptional processes, replication has proven to be key for 53BP1 NBs, with replication stress leading to the formation of these large chromatin domains in daughter cells. In this review, we expose the composition and organization of 53BP1 NBs and focus on recent findings regarding their regulation and dynamics. We then concentrate on the importance of the replication stress, examine the relation of 53BP1 NBs with DNA damage and discuss their dysfunction.
Topics: Animals; Cell Nucleus; Chromatin; DNA Damage; DNA Replication; Humans; Tumor Suppressor p53-Binding Protein 1
PubMed: 29206178
DOI: 10.3390/ijms18122611 -
Advances in Cancer Research 2021The use of DNA-damaging agents such as radiotherapy and chemotherapy has been a mainstay treatment protocol for many cancers, including lung and prostate. Recently, FDA... (Review)
Review
The use of DNA-damaging agents such as radiotherapy and chemotherapy has been a mainstay treatment protocol for many cancers, including lung and prostate. Recently, FDA approval of inhibitors of DNA repair, and targeting innate immunity to enhance the efficacy of DNA-damaging agents have gained much attention. Yet, inherent or acquired resistance against DNA-damaging therapies persists as a fundamental drawback. While cancer eradication by causing cancer cell death through induction of apoptosis is the ultimate goal of anti-cancer treatments, autophagy and senescence are two major cellular responses induced by clinically tolerable doses of DNA-damaging therapies. Unlike apoptosis, autophagy and senescence can act as both pro-tumorigenic as well as tumor suppressive mechanisms. DNA damage-induced senescence is associated with a pro-inflammatory secretory phenotype, which contributes to reshaping the tumor- immune microenvironment. Moreover, PTEN (phosphatase and tensin homolog) is a tumor supressor deleted in many tumors, and has been implicated in both senescence and autophagy. This review presents an overview of the literature on the regulation and consequences of DNA damage- induced senescence in cancer cells, with a specific focus on autophagy and PTEN. Both autophagy and senescence occur concurrently in the same cells in response to DNA damaging agents. However, a deterministic relationship between these fundamental processes has been controversial. We present experimental evidence obtained with tumor cells, with a prime focus on two models of cancer, prostate and lung. A better understanding of mechanisms associated with DNA damage-induced cellular senescence is central to fully exploit the potential of DNA-damaging agents against cancer.
Topics: Animals; Apoptosis; Autophagy; Cellular Senescence; DNA Damage; Female; Humans; Male; PTEN Phosphohydrolase; Signal Transduction; Tumor Microenvironment
PubMed: 33858598
DOI: 10.1016/bs.acr.2021.01.006 -
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... Sep 2019Nickel (Ni) is known to be a major carcinogenic heavy metal. Occupational and environmental exposure to Ni has been implicated in human lung and nasal cancers.... (Review)
Review
Nickel (Ni) is known to be a major carcinogenic heavy metal. Occupational and environmental exposure to Ni has been implicated in human lung and nasal cancers. Currently, the molecular mechanisms of Ni carcinogenicity remain unclear, but studies have shown that Ni-caused DNA damage is an important carcinogenic mechanism. Therefore, we conducted a literature search of DNA damage associated with Ni exposure and summarized known Ni-caused DNA damage effects. In vitro and vivo studies demonstrated that Ni can induce DNA damage through direct DNA binding and reactive oxygen species (ROS) stimulation. Ni can also repress the DNA damage repair systems, including direct reversal, nucleotide repair (NER), base excision repair (BER), mismatch repair (MMR), homologous-recombination repair (HR), and nonhomologous end-joining (NHEJ) repair pathways. The repression of DNA repair is through direct enzyme inhibition and the downregulation of DNA repair molecule expression. Up to now, the exact mechanisms of DNA damage caused by Ni and Ni compounds remain unclear. Revealing the mechanisms of DNA damage from Ni exposure may contribute to the development of preventive strategies in Ni carcinogenicity.
Topics: Animals; Carcinogenesis; DNA Breaks, Double-Stranded; DNA Damage; DNA Mismatch Repair; DNA Repair; Humans; Nickel; Reactive Oxygen Species
PubMed: 31546657
DOI: 10.3390/ijms20194690