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Genes & Development Feb 2022Genomic DNA is continuously challenged by endogenous and exogenous sources of damage. The resulting lesions may act as physical blocks to DNA replication, necessitating... (Review)
Review
Genomic DNA is continuously challenged by endogenous and exogenous sources of damage. The resulting lesions may act as physical blocks to DNA replication, necessitating repair mechanisms to be intrinsically coupled to the DNA replisome machinery. DNA damage tolerance (DDT) is comprised of translesion synthesis (TLS) and template switch (TS) repair processes that allow the replisome to bypass of bulky DNA lesions and complete DNA replication. How the replisome orchestrates which DDT repair mechanism becomes active at replication blocks has remained enigmatic. In this issue of , Dolce and colleagues (pp. 167-179) report that parental histone deposition by replisome components Ctf4 and Dpb3/4 promotes TS while suppressing error-prone TLS. Deletion of Dpb3/4 restored resistance to DNA-damaging agents in Δ cells at the expense of synergistic increases in mutagenesis due to elevated TLS. These findings illustrate the importance of replisome-directed chromatin maintenance to genome integrity and the response to DNA-damaging anticancer therapeutics.
Topics: DNA; DNA Damage; DNA Repair; DNA Replication
PubMed: 35193944
DOI: 10.1101/gad.349408.122 -
Nature Reviews. Molecular Cell Biology May 2021
Topics: Brain; DNA; DNA Damage; DNA Repair; Regulatory Sequences, Nucleic Acid
PubMed: 33828243
DOI: 10.1038/s41580-021-00367-5 -
Current Opinion in Biotechnology Feb 2019Detection and characterization of DNA damage is essential for evaluating genotoxicity, monitoring DNA repair, developing biomarkers for exposures, and evaluating the... (Review)
Review
Detection and characterization of DNA damage is essential for evaluating genotoxicity, monitoring DNA repair, developing biomarkers for exposures, and evaluating the efficacy of chemotherapies. These diverse applications for DNA damage measurements have spurred the continual development and refinement of methodologies for detecting, characterizing, and quantifying DNA damage from isolated DNA and in cells and tissues. Current damage detection methods cover a wide range of techniques from radiolabeling to mass spectrometry, and use of these techniques varies widely based on expense, expertise, and knowledge of adduct formation. More generalizable, easy-to-use methods for detecting and quantifying DNA damage are needed, and there has been an emergence of fluorescence-based methodologies to address this need. Developments in these fluorescence-based strategies are reviewed here.
Topics: Biomarkers; DNA Adducts; DNA Damage; DNA Repair; Enzyme Assays; Fluorescence; Humans
PubMed: 30114673
DOI: 10.1016/j.copbio.2018.08.001 -
Mutation Research Jun 2011DNA damage plays a major role in various pathophysiological conditions including carcinogenesis, aging, inflammation, diabetes and neurodegenerative diseases. Oxidative... (Review)
Review
DNA damage plays a major role in various pathophysiological conditions including carcinogenesis, aging, inflammation, diabetes and neurodegenerative diseases. Oxidative stress and cell processes such as lipid peroxidation and glycation induce the formation of highly reactive endogenous aldehydes that react directly with DNA, form aldehyde-derived DNA adducts and lead to DNA damage. In occasion of persistent conditions that influence the formation and accumulation of aldehyde-derived DNA adducts the resulting unrepaired DNA damage causes deregulation of cell homeostasis and thus significantly contributes to disease phenotype. Some of the most highly reactive aldehydes produced endogenously are 4-hydroxy-2-nonenal, malondialdehyde, acrolein, crotonaldehyde and methylglyoxal. The mutagenic and carcinogenic effects associated with the elevated levels of these reactive aldehydes, especially, under conditions of stress, are attributed to their capability of causing directly modification of DNA bases or yielding promutagenic exocyclic adducts. In this review, we discuss the current knowledge on DNA damage induced by endogenously produced reactive aldehydes in relation to the pathophysiology of human diseases.
Topics: Aldehydes; Animals; DNA Adducts; DNA Damage; Humans
PubMed: 21419140
DOI: 10.1016/j.mrfmmm.2011.03.006 -
Photodermatology, Photoimmunology &... May 2017There is strong evidence that topical sunscreens, designed to protect against ultraviolet radiation (UVR)-induced erythema, decrease the amount of UVR to which the skin... (Review)
Review
BACKGROUND/PURPOSE
There is strong evidence that topical sunscreens, designed to protect against ultraviolet radiation (UVR)-induced erythema, decrease the amount of UVR to which the skin is exposed, but their effectiveness in reducing UVR-induced DNA damage in vivo has not been well quantified.
METHODS
We systematically reviewed the published literature (1990-2015) to determine whether sunscreens prevent DNA damage in human skin when applied prior to UVR exposure. We included experimental studies measuring UVR-induced DNA damage in human skin in vivo with and without sunscreens and excluded studies conducted in animal models and cell lines. Eligible studies were identified by computerized search of bibliographic databases, supplemented by hand-searching the reference lists of retrieved articles.
RESULTS
We identified ten eligible studies. Despite heterogeneity in methodological approaches, including the sun protection factors of the sunscreens assessed, range of skin types examined, the UVR exposure time and dose, the timing of post-irradiation biopsies and in the markers of DNA damage examined, all studies reported markedly reduced (or nil) UVR-induced DNA damage on sunscreen-protected skin.
CONCLUSION
Our review of the experimental evidence supports a protective effect of topical sunscreens in preventing UVR-induced DNA damage in human skin cells in vivo.
Topics: DNA Damage; Humans; Sunscreening Agents; Ultraviolet Rays
PubMed: 28165636
DOI: 10.1111/phpp.12298 -
Biochemical Society Transactions Aug 2009Ion-beam irradiation provides a promising treatment for some types of cancer. This promise is due mainly to the selective deposition of energy into a relatively small... (Review)
Review
Ion-beam irradiation provides a promising treatment for some types of cancer. This promise is due mainly to the selective deposition of energy into a relatively small volume (the Bragg peak), thus reducing damage to healthy tissue. Recent observations that electrons with energies below the ionization potential of DNA can cause covalent damage to the bases and backbone have led to investigations into the ability of low-energy (<1 keV x Da(-1)) ion beams to damage double-stranded DNA. It has been clearly demonstrated that these low-energy ions induce a mixture of single- and double-strand breaks to dried DNA in vacuo. These effects depend upon the number of ions incident upon the DNA, the kinetic energy of the ions and on their charge state. This DNA damage may be important, as all radiotherapies will result in the production of low-energy secondary ions as radiation passes through tissues. Currently, their effects are neglected in treatment planning, and thus more work is required to quantify and understand DNA damage by low-energy ions.
Topics: Animals; DNA Breaks, Double-Stranded; DNA Damage; Humans; Ions; Models, Theoretical
PubMed: 19614614
DOI: 10.1042/BST0370893 -
Methods in Molecular Biology (Clifton,... 2022Development of B cells requires the programmed generation and repair of double-stranded DNA breaks in antigen receptor genes. Investigation of the cellular responses to...
Development of B cells requires the programmed generation and repair of double-stranded DNA breaks in antigen receptor genes. Investigation of the cellular responses to these DNA breaks has established important insights into B cell development and, more broadly, has provided fundamental advances into the molecular mechanisms of DNA damage response pathways. Abelson transformed pre-B cell lines and primary pre-B cell cultures are malleable experimental systems with diverse applications for studying DNA damage responses. This chapter describes methods for generating these cellular systems, inducing and quantifying DSBs, and assessing DNA damage programs.
Topics: B-Lymphocytes; DNA Breaks, Double-Stranded; DNA Damage; Humans; Lymphoma, B-Cell; Receptors, Antigen
PubMed: 35290632
DOI: 10.1007/978-1-0716-2063-2_5 -
Mutation Research. Reviews in Mutation... 2021About 40 million workers are occupationally exposed to crystalline silica (CS) which was classified as a human carcinogen by the IARC. It is assumed that damage of the... (Meta-Analysis)
Meta-Analysis Review
About 40 million workers are occupationally exposed to crystalline silica (CS) which was classified as a human carcinogen by the IARC. It is assumed that damage of the genetic material via inflammation and reactive oxygen species by CS lead to formation of malignant cells. We conducted a systematic literature search to find out if inhalation of CS containing dusts at workplaces causes damage of the genetic material. Thirteen studies were found eligible for this review, in most of them (n = 9) micronuclei (MN) which reflect structural/numerical chromosomal aberrations were monitored in lymphocytes and/or in exfoliated buccal cells. In 5 investigations DNA damage was measured in blood cells in single cell gel electrophoresis (comet) experiments. Frequently studied groups were potters, stone cutters, miners and construction workers. Results of meta-analyses show that exposure to CS causes formation of MN and DNA breaks, the overall ratio values were in exposed workers 2.06- and 1.96-fold higher than in controls, respectively. Two studies reported increased levels of oxidized guanine, and higher levels of DNA adducts with malondialdehyde indicating that exposure to CS leads to oxidative damage. The exposure of the workers to CS was quantified only in two studies, information concerning the size and chemical structures of the particles is lacking in most investigations. Therefore, it is not possible to use the results to derive occupational exposure limits of workers to CS which vary strongly in different countries. Nevertheless, the evaluation of the current state of knowledge shows that biomonitoring studies in which damage of the genetic material is measured in CS exposed workers can contribute to assess adverse health effects as consequence of DNA instability in specific occupations.
Topics: Comet Assay; DNA Damage; Micronuclei, Chromosome-Defective; Silicon Dioxide
PubMed: 34083037
DOI: 10.1016/j.mrrev.2020.108349 -
Alcoholism, Clinical and Experimental... Sep 1997Alcohol (ethanol) is clearly a toxic substance when consumed in excess. Chronic alcohol abuse results in a variety of pathological effects, including damage to the liver... (Review)
Review
Alcohol (ethanol) is clearly a toxic substance when consumed in excess. Chronic alcohol abuse results in a variety of pathological effects, including damage to the liver and brain, as well as other organs, and is associated with an increased risk of certain types of cancers. Alcohol consumption by pregnant women can result in fetal alcohol effects and fetal alcohol syndrome. All of these toxic effects are well documented. What is needed at present is a complete understanding of the molecular mechanisms by which alcohol causes these toxic effects. Such an understanding may lead to better treatments of some of these toxic effects. This review, focuses on the possibility that toxic effects of ethanol are mediated, at least in part, by damage to DNA. In particular, I emphasize data on the production of endogenous DNA-damaging molecules as a result of alcohol consumption and metabolism. Specific examples of DNA-damaging molecules to be considered are reactive oxygen species, including oxygen radicals, lipid peroxidation products, and acetaldehyde. The relevant DNA repair pathways that protect cells against DNA damage produced by these molecules will also be reviewed. The goal of this review is to integrate recent results from the fields of mutagenesis and DNA repair with the alcohol toxicity literature, with the aim of stimulating research into the role of DNA damage in different types of alcohol toxicity and the role of DNA repair in protecting cells from alcohol-related damage.
Topics: Animals; Carcinogenicity Tests; DNA Adducts; DNA Damage; DNA Repair; Ethanol; Female; Humans; Infant, Newborn; Lipid Peroxidation; Pregnancy
PubMed: 9309320
DOI: No ID Found -
Cells Feb 2021NIMA-related kinases, or NEKs, are a family of Ser/Thr protein kinases involved in cell cycle and mitosis, centrosome disjunction, primary cilia functions, and DNA... (Review)
Review
NIMA-related kinases, or NEKs, are a family of Ser/Thr protein kinases involved in cell cycle and mitosis, centrosome disjunction, primary cilia functions, and DNA damage responses among other biological functional contexts in vertebrate cells. In human cells, there are 11 members, termed NEK1 to 11, and the research has mainly focused on exploring the more predominant roles of NEKs in mitosis regulation and cell cycle. A possible important role of NEKs in DNA damage response (DDR) first emerged for NEK1, but recent studies for most NEKs showed participation in DDR. A detailed analysis of the protein interactions, phosphorylation events, and studies of functional aspects of NEKs from the literature led us to propose a more general role of NEKs in DDR. In this review, we express that NEK1 is an activator of ataxia telangiectasia and Rad3-related (ATR), and its activation results in cell cycle arrest, guaranteeing DNA repair while activating specific repair pathways such as homology repair (HR) and DNA double-strand break (DSB) repair. For NEK2, 6, 8, 9, and 11, we found a role downstream of ATR and ataxia telangiectasia mutated (ATM) that results in cell cycle arrest, but details of possible activated repair pathways are still being investigated. NEK4 shows a connection to the regulation of the nonhomologous end-joining (NHEJ) repair of DNA DSBs, through recruitment of DNA-PK to DNA damage foci. NEK5 interacts with topoisomerase IIβ, and its knockdown results in the accumulation of damaged DNA. NEK7 has a regulatory role in the detection of oxidative damage to telomeric DNA. Finally, NEK10 has recently been shown to phosphorylate p53 at Y327, promoting cell cycle arrest after exposure to DNA damaging agents. In summary, this review highlights important discoveries of the ever-growing involvement of NEK kinases in the DDR pathways. A better understanding of these roles may open new diagnostic possibilities or pharmaceutical interventions regarding the chemo-sensitizing inhibition of NEKs in various forms of cancer and other diseases.
Topics: DNA Damage; DNA Repair; Humans
PubMed: 33673578
DOI: 10.3390/cells10030507