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Mutation Research Oct 2013Cells are equipped with a cell-intrinsic signaling network called the DNA damage response (DDR). This signaling network recognizes DNA lesions and initiates various... (Review)
Review
Cells are equipped with a cell-intrinsic signaling network called the DNA damage response (DDR). This signaling network recognizes DNA lesions and initiates various downstream pathways to coordinate a cell cycle arrest with the repair of the damaged DNA. Alternatively, the DDR can mediate clearance of affected cells that are beyond repair through apoptosis or senescence. The DDR can be activated in response to DNA damage throughout the cell cycle, although the extent of DDR signaling is different in each cell cycle phase. Especially in response to DNA double strand breaks, only a very marginal response was observed during mitosis. Early on it was recognized that cells which are irradiated during mitosis continued division without repairing broken chromosomes. Although these initial observations indicated diminished DNA repair and lack of an acute DNA damage-induced cell cycle arrest, insight into the mechanistic re-wiring of DDR signaling during mitosis was only recently provided. Different mechanisms appear to be at play to inactivate specific signaling axes of the DDR network in mitosis. Importantly, mitotic cells not simply inactivate the entire DDR, but appear to mark their DNA damage for repair after mitotic exit. Since the treatment of cancer frequently involves agents that induce DNA damage as well as agents that block mitotic progression, it is clinically relevant to obtain a better understanding of how cancer cells deal with DNA damage during interphase versus mitosis. In this review, the molecular details concerning DDR signaling during mitosis as well as the consequences of encountering DNA damage during mitosis for cellular fate are discussed.
Topics: Animals; Cell Cycle; Cell Cycle Proteins; DNA Breaks, Double-Stranded; DNA Damage; DNA Repair; Humans; Mitosis; Models, Biological; Signal Transduction
PubMed: 23880065
DOI: 10.1016/j.mrfmmm.2013.07.003 -
Journal of Cellular Physiology Dec 2007Studies on DNA damage responses in proliferating cells have revealed the relationship between sensing and repair of the DNA lesions and the regulation of the cell cycle,... (Review)
Review
Studies on DNA damage responses in proliferating cells have revealed the relationship between sensing and repair of the DNA lesions and the regulation of the cell cycle, leading to the discovery and molecular characterization of the DNA damage-activated cell cycle checkpoints. Much less is known about the DNA damage response in progenitors of differentiated cells, in which cell cycle arrest is a critical signal to trigger the differentiation program, and in terminally differentiated cells, which are typically post-mitotic. How DNA lesions are detected, processed and repaired in these cells, the functional impact of DNA damage on transcription of differentiation-specific genes, how these events are coordinated at the molecular level, the consequence of defective DNA damage response on tissue-specific functions and its potential relationship with age-related diseases are currently open questions. In particular the biological complexity inherent to the global genome reprogramming of tissue progenitors, such as embryonic or adult stem cells, suggests the importance of an accurate DNA damage response at the transcription level in these cells to ensure the genomic integrity of regenerating tissues.
Topics: Animals; Cell Differentiation; DNA Damage; Humans; Models, Biological
PubMed: 17894406
DOI: 10.1002/jcp.21275 -
The Enzymes 2022DNA is under a variety of assaults. As a result, different damages accumulate on DNA. These include base changes, single-strand breaks and double-strand breaks. In this...
DNA is under a variety of assaults. As a result, different damages accumulate on DNA. These include base changes, single-strand breaks and double-strand breaks. In this volume and also briefly in the following volume, we discuss DNA damage and double-strand breaks. In particular, we focus on double-strand breaks. We discuss types of double-strand breaks as well as methods to detect them. We also discuss how DNA breaks are formed.
Topics: DNA Damage; DNA Repair; DNA
PubMed: 36336403
DOI: 10.1016/bs.enz.2022.08.001 -
Metallomics : Integrated Biometal... Aug 2014The redox activity of metal ions can lead to the formation of highly reactive species that damage DNA, producing different oxidation products and types of damage... (Review)
Review
The redox activity of metal ions can lead to the formation of highly reactive species that damage DNA, producing different oxidation products and types of damage depending upon the redox potentials of the DNA bases, formation of intermediate adducts, and identity of the reactive species. Other factors are also important in determining the degree of metal-mediated DNA damage, such as localization and redox chemistry of the metal ions or complexes and lifetimes of the reactive oxygen species generated. This review examines the types of DNA damage mediated by first-row transition metals under oxidative stress conditions, with emphasis on work published in the past ten years. Similarities and differences between DNA damage mechanisms of the first-row transition metals in vitro and in E. coli and human cells are compared and their relationship to disease development are discussed. Methods to detect this metal-mediated DNA damage, including backbone breakage, base oxidation, inter- and intra-strand crosslinking, and DNA-protein crosslinking are also briefly reviewed, as well as detection methods for reactive oxygen species generated by these metal ions. Understanding the conditions that cause metal-mediated DNA damage and metal generation of reactive oxygen species in vitro and in cells is required to develop effective drugs to prevent and treat chronic disease.
Topics: DNA; DNA Damage; Escherichia coli; Humans; Oxidative Stress; Proteins
PubMed: 24788233
DOI: 10.1039/c4mt00057a -
Mutation Research Mar 1999Estrogen administration to rodents results in various types of DNA damage and ultimately leads to tumors in estrogen-responsive tissues. Yet these hormones have been... (Review)
Review
Estrogen administration to rodents results in various types of DNA damage and ultimately leads to tumors in estrogen-responsive tissues. Yet these hormones have been classified as nonmutagenic, because they did not induce mutations in classical bacterial and mammalian mutation assays. In this review, we have discussed the induction by estrogens of DNA and chromosomal damage and of gene mutations, because the classical assays were designed to uncover mutations only at one specific locus and could not have detected other types of mutations or changes in other genes. Various types of estrogen-induced DNA damage include: (a) direct covalent binding of estrogen quinone metabolites to DNA; (b) enhancement of endogenous DNA adducts by chronic estrogen exposure of rodents; (c) free radical generation by metabolic redox cycling between quinone and hydroquinone forms of estrogens and free radical damage to DNA such as strand breakage, 8-hydroxylation of purine bases of DNA and lipid hydroperoxide-mediated DNA modification. Two different types of chromosomal damage have also been induced by estrogen in vivo and in cells in culture such as numerical chromosomal changes and also structural chromosomal aberrations. Gene mutations have been induced in several cell types in culture either by the parent estrogen or by reactive estrogen quinone metabolites. Furthermore, in estrogen-induced kidney tumors in hamsters, several mutations have been observed in the DNA polymerase beta gene mRNA. Estradiol also induces microsatellite instability in these kidney tumors and in premalignant kidney exposed to estradiol. Although this work is still ongoing, it can be concluded that estrogens are complete carcinogens capable of tumor initiation by mutation potentially in critical genes. The hormonal effects of estrogens may complete the development of tumors.
Topics: Animals; Chromosome Aberrations; Cricetinae; DNA Adducts; DNA Damage; Estrogens; Mutation
PubMed: 10064854
DOI: 10.1016/s0027-5107(99)00012-3 -
Current Opinion in Genetics &... Feb 2004Disruption of the mechanisms that regulate cell-cycle checkpoints, DNA repair, and apoptosis results in genomic instability and the development of cancer in... (Review)
Review
Disruption of the mechanisms that regulate cell-cycle checkpoints, DNA repair, and apoptosis results in genomic instability and the development of cancer in multicellular organisms. The protein kinases ATM and ATR, as well as their downstream substrates Chk1 and Chk2, are central players in checkpoint activation in response to DNA damage. Histone H2AX, ATRIP, as well as the BRCT-motif-containing molecules 53BP1, MDC1, and BRCA1 function as molecular adapters or mediators in the recruitment of ATM or ATR and their targets to sites of DNA damage. The increased chromosomal instability and tumor susceptibility apparent in mutant mice deficient in both p53 and either histone H2AX or proteins that contribute to the nonhomologous end-joining mechanism of DNA repair indicate that DNA damage checkpoints play a pivotal role in tumor suppression.
Topics: Animals; Apoptosis; DNA Damage; DNA Repair; Genes, Tumor Suppressor; Genes, cdc; Genomic Instability
PubMed: 15108799
DOI: 10.1016/j.gde.2003.12.003 -
Seminars in Cancer Biology Oct 2006The genome is constantly exposed to exogenous DNA damaging events in the form of radiation, viral infection and chemicals. Endogenous processes such as DNA replication... (Review)
Review
The genome is constantly exposed to exogenous DNA damaging events in the form of radiation, viral infection and chemicals. Endogenous processes such as DNA replication and free radical formation also threaten the integrity of the genome. DNA damage is directly deleterious to cells and also promotes tumorigenesis. Eukaryotic organisms have evolved a signaling pathway, called the DNA damage response, to protect against genomic insults. Sensor proteins detect various forms of damage, and convey signals via a complex pathway regulated by protein phosphorylation, stabilization and transcriptional regulation. The DNA damage response causes cell cycle arrest and induction of DNA repair functions, such that cells with modest damage may survive. However, cells with more severe damage are induced to undergo apoptosis. Two compelling studies show that the DNA damage response is activated very early during tumorigenesis, providing evidence that the DNA damage response could function as a barrier in early tumorigenesis. We recently demonstrated that the DNA damage response alerts the immune system by inducing expression of cell surface ligands for the activating immune receptor NKG2D, which is expressed by natural killer cells (NK cells) and some T cells. In this review we discuss the DNA damage response and its link to the innate immune system and tumor surveillance. These findings might have important implications for the understanding of cancer therapies and for drug development.
Topics: Animals; DNA Damage; DNA Repair; Humans; Immunity, Cellular; Ligands; Models, Biological; NK Cell Lectin-Like Receptor Subfamily K; Neoplasms; Receptors, Immunologic; Receptors, Natural Killer Cell
PubMed: 16914325
DOI: 10.1016/j.semcancer.2006.07.004 -
Trends in Cell Biology Jul 2000DNA damage causes cell-cycle delay before S phase, during replication and before mitosis. This involves a number of highly conserved proteins that sense DNA damage and... (Review)
Review
DNA damage causes cell-cycle delay before S phase, during replication and before mitosis. This involves a number of highly conserved proteins that sense DNA damage and signal the cell-cycle machinery. Kinases that were initially discovered in yeast model systems have recently been shown to regulate the regulators of cyclin-dependent kinases and to control the stability of p53. This shows the importance of checkpoint proteins for maintaining genome stability. Here, we discuss recent data from yeast and metazoans that suggest a remarkable conservation of the organization of the G2 DNA-damage checkpoint pathway.
Topics: Animals; Cell Physiological Phenomena; DNA Damage; G2 Phase
PubMed: 10856933
DOI: 10.1016/s0962-8924(00)01773-6 -
Aging Feb 2021Failure of rapamycin to extend lifespan in DNA repair mutant and telomerase-knockout mice, while extending lifespan in normal mice, indicates that neither DNA damage nor...
Failure of rapamycin to extend lifespan in DNA repair mutant and telomerase-knockout mice, while extending lifespan in normal mice, indicates that neither DNA damage nor telomere shortening limits normal lifespan or causes normal aging.
Topics: Animals; DNA Damage; Longevity; Mice; Mice, Knockout; Sirolimus; Telomere
PubMed: 33578394
DOI: 10.18632/aging.202674 -
International Journal of Molecular... Jun 2018
Topics: Animals; DNA Damage; DNA Repair; Humans; Mutagenesis; Neoplasms
PubMed: 29899224
DOI: 10.3390/ijms19061767