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Environmental and Molecular Mutagenesis Jun 2017Living organisms are continuously exposed to a myriad of DNA damaging agents that can impact health and modulate disease-states. However, robust DNA repair and... (Review)
Review
Living organisms are continuously exposed to a myriad of DNA damaging agents that can impact health and modulate disease-states. However, robust DNA repair and damage-bypass mechanisms faithfully protect the DNA by either removing or tolerating the damage to ensure an overall survival. Deviations in this fine-tuning are known to destabilize cellular metabolic homeostasis, as exemplified in diverse cancers where disruption or deregulation of DNA repair pathways results in genome instability. Because routinely used biological, physical and chemical agents impact human health, testing their genotoxicity and regulating their use have become important. In this introductory review, we will delineate mechanisms of DNA damage and the counteracting repair/tolerance pathways to provide insights into the molecular basis of genotoxicity in cells that lays the foundation for subsequent articles in this issue. Environ. Mol. Mutagen. 58:235-263, 2017. © 2017 Wiley Periodicals, Inc.
Topics: Animals; DNA Damage; DNA Repair; Humans; Mutagenesis; Telomere
PubMed: 28485537
DOI: 10.1002/em.22087 -
Nature Oct 2009The prime objective for every life form is to deliver its genetic material, intact and unchanged, to the next generation. This must be achieved despite constant assaults... (Review)
Review
The prime objective for every life form is to deliver its genetic material, intact and unchanged, to the next generation. This must be achieved despite constant assaults by endogenous and environmental agents on the DNA. To counter this threat, life has evolved several systems to detect DNA damage, signal its presence and mediate its repair. Such responses, which have an impact on a wide range of cellular events, are biologically significant because they prevent diverse human diseases. Our improving understanding of DNA-damage responses is providing new avenues for disease management.
Topics: Cell Cycle; DNA Damage; DNA Repair; Disease; Genome, Human; Humans; Signal Transduction
PubMed: 19847258
DOI: 10.1038/nature08467 -
EXS 2009A genotoxin is a chemical or agent that can cause DNA or chromosomal damage. Such damage in a germ cell has the potential to cause a heritable altered trait (germline... (Review)
Review
A genotoxin is a chemical or agent that can cause DNA or chromosomal damage. Such damage in a germ cell has the potential to cause a heritable altered trait (germline mutation). DNA damage in a somatic cell may result in a somatic mutation, which may lead to malignant transformation (cancer). Many in vitro and in vivo tests for genotoxicity have been developed that, with a range of endpoints, detect DNA damage or its biological consequences in prokaryotic (e.g. bacterial) or eukaryotic (e.g. mammalian, avian or yeast) cells. These assays are used to evaluate the safety of environmental chemicals and consumer products and to explore the mechanism of action of known or suspected carcinogens. Many chemical carcinogens/mutagens undergo metabolic activation to reactive species that bind covalently to DNA, and the DNA adducts thus formed can be detected in cells and in human tissues by a variety of sensitive techniques. The detection and characterisation of DNA adducts in human tissues provides clues to the aetiology of human cancer. Characterisation of gene mutations in human tumours, in common with the known mutagenic profiles of genotoxins in experimental systems, may provide further insight into the role of environmental mutagens in human cancer.
Topics: Animals; Carcinogens; DNA Adducts; DNA Damage; Environmental Pollutants; Mutagenicity Tests; Mutagens; Toxicogenetics
PubMed: 19157059
DOI: 10.1007/978-3-7643-8336-7_4 -
ELife Jan 2021Aging is a complex process that results in loss of the ability to reattain homeostasis following stress, leading, thereby, to increased risk of morbidity and mortality.... (Review)
Review
Aging is a complex process that results in loss of the ability to reattain homeostasis following stress, leading, thereby, to increased risk of morbidity and mortality. Many factors contribute to aging, such as the time-dependent accumulation of macromolecular damage, including DNA damage. The integrity of the nuclear genome is essential for cellular, tissue, and organismal health. DNA damage is a constant threat because nucleic acids are chemically unstable under physiological conditions and vulnerable to attack by endogenous and environmental factors. To combat this, all organisms possess highly conserved mechanisms to detect and repair DNA damage. Persistent DNA damage (genotoxic stress) triggers signaling cascades that drive cells into apoptosis or senescence to avoid replicating a damaged genome. The drawback is that these cancer avoidance mechanisms promote aging. Here, we review evidence that DNA damage plays a causal role in aging. We also provide evidence that genotoxic stress is linked to other cellular processes implicated as drivers of aging, including mitochondrial and metabolic dysfunction, altered proteostasis and inflammation. These links between damage to the genetic code and other pillars of aging support the notion that DNA damage could be the root of aging.
Topics: Aging; Animals; DNA Damage; Humans; Inflammation; Proteostasis
PubMed: 33512317
DOI: 10.7554/eLife.62852 -
International Journal of Molecular... Mar 2018A large number of chemicals and several physical agents, such as UV light and γ-radiation, have been associated with the etiology of human cancer. Generation of DNA... (Review)
Review
A large number of chemicals and several physical agents, such as UV light and γ-radiation, have been associated with the etiology of human cancer. Generation of DNA damage (also known as DNA adducts or lesions) induced by these agents is an important first step in the process of carcinogenesis. Evolutionary processes gave rise to DNA repair tools that are efficient in repairing damaged DNA; yet replication of damaged DNA may take place prior to repair, particularly when they are induced at a high frequency. Damaged DNA replication may lead to gene mutations, which in turn may give rise to altered proteins. Mutations in an oncogene, a tumor-suppressor gene, or a gene that controls the cell cycle can generate a clonal cell population with a distinct advantage in proliferation. Many such events, broadly divided into the stages of initiation, promotion, and progression, which may occur over a long period of time and transpire in the context of chronic exposure to carcinogens, can lead to the induction of human cancer. This is exemplified in the long-term use of tobacco being responsible for an increased risk of lung cancer. This mini-review attempts to summarize this wide area that centers on DNA damage as it relates to the development of human cancer.
Topics: DNA Adducts; DNA Damage; Humans; Mutagenesis; Neoplasms
PubMed: 29570697
DOI: 10.3390/ijms19040970 -
Cell Metabolism Dec 2014Accumulation of DNA damage has been linked to the process of aging and to the onset of age-related diseases including diabetes. Studies on progeroid syndromes have... (Review)
Review
Accumulation of DNA damage has been linked to the process of aging and to the onset of age-related diseases including diabetes. Studies on progeroid syndromes have suggested that the DNA damage response is involved in regulation of metabolic homeostasis. DNA damage could impair metabolic organ functions by causing cell death or senescence. DNA damage also could induce tissue inflammation that disturbs the homeostasis of systemic metabolism. Various roles of molecules related to DNA repair in cellular metabolism are being uncovered, and such molecules could also have an impact on systemic metabolism. This review explores mechanisms by which the DNA damage response could contribute to metabolic dysfunction.
Topics: Animals; DNA Damage; DNA Repair; Humans; Metabolic Diseases
PubMed: 25456739
DOI: 10.1016/j.cmet.2014.10.008 -
DNA Repair Feb 2016This review discusses the role of DNA mismatch repair (MMR) in the DNA damage response (DDR) that triggers cell cycle arrest and, in some cases, apoptosis. Although the... (Review)
Review
This review discusses the role of DNA mismatch repair (MMR) in the DNA damage response (DDR) that triggers cell cycle arrest and, in some cases, apoptosis. Although the focus is on findings from mammalian cells, much has been learned from studies in other organisms including bacteria and yeast [1,2]. MMR promotes a DDR mediated by a key signaling kinase, ATM and Rad3-related (ATR), in response to various types of DNA damage including some encountered in widely used chemotherapy regimes. An introduction to the DDR mediated by ATR reveals its immense complexity and highlights the many biological and mechanistic questions that remain. Recent findings and future directions are highlighted.
Topics: Animals; DNA Adducts; DNA Damage; DNA Methylation; DNA Mismatch Repair; Humans; Signal Transduction
PubMed: 26704428
DOI: 10.1016/j.dnarep.2015.11.019 -
Cells Jul 2020DNA is the source of genetic information, and preserving its integrity is essential in order to sustain life. The genome is continuously threatened by different types of... (Review)
Review
DNA is the source of genetic information, and preserving its integrity is essential in order to sustain life. The genome is continuously threatened by different types of DNA lesions, such as abasic sites, mismatches, interstrand crosslinks, or single-stranded and double-stranded breaks. As a consequence, cells have evolved specialized DNA damage response (DDR) mechanisms to sustain genome integrity. By orchestrating multilayer signaling cascades specific for the type of lesion that occurred, the DDR ensures that genetic information is preserved overtime. In the last decades, DNA repair mechanisms have been thoroughly investigated to untangle these complex networks of pathways and processes. As a result, key factors have been identified that control and coordinate DDR circuits in time and space. In the first part of this review, we describe the critical processes encompassing DNA damage sensing and resolution. In the second part, we illustrate the consequences of partial or complete failure of the DNA repair machinery. Lastly, we will report examples in which this knowledge has been instrumental to develop novel therapies based on genome editing technologies, such as CRISPR-Cas.
Topics: Animals; Clustered Regularly Interspaced Short Palindromic Repeats; DNA Damage; DNA Repair; Gene Editing; Humans
PubMed: 32664329
DOI: 10.3390/cells9071665 -
Molecular Cell Oct 2010Damage to our genetic material is an ongoing threat to both our ability to faithfully transmit genetic information to our offspring as well as our own survival. To... (Review)
Review
Damage to our genetic material is an ongoing threat to both our ability to faithfully transmit genetic information to our offspring as well as our own survival. To respond to these threats, eukaryotes have evolved the DNA damage response (DDR). The DDR is a complex signal transduction pathway that has the ability to sense DNA damage and transduce this information to the cell to influence cellular responses to DNA damage. Cells possess an arsenal of enzymatic tools capable of remodeling and repairing DNA; however, their activities must be tightly regulated in a temporal, spatial, and DNA lesion-appropriate fashion to optimize repair and prevent unnecessary and potentially deleterious alterations in the structure of DNA during normal cellular processes. This review will focus on how the DDR controls DNA repair and the phenotypic consequences of defects in these critical regulatory functions in mammals.
Topics: Animals; DNA; DNA Breaks, Double-Stranded; DNA Damage; DNA Repair; Eukaryota; Models, Genetic; Recombination, Genetic; Signal Transduction
PubMed: 20965415
DOI: 10.1016/j.molcel.2010.09.019 -
Neural Plasticity 2016
Topics: Animals; DNA Damage; Humans; Nerve Degeneration; Neuronal Plasticity
PubMed: 27313899
DOI: 10.1155/2016/1206840