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Philosophical Transactions of the Royal... Nov 1996Although DNA is the carrier of stable genetic information, this giant molecule exhibits slow turnover in cells as a consequence of endogenous damage. DNA lesions result... (Review)
Review
Although DNA is the carrier of stable genetic information, this giant molecule exhibits slow turnover in cells as a consequence of endogenous damage. DNA lesions result from hydrolysis, and from exposure to active oxygen and reactive metabolites. These major forms of damage to the heterocyclic bases and to the DNA backbone structure are now well characterized. Most DNA repair enzymes have apparently evolved to prevent genomic instability caused by endogenous lesions, the only exception being those that counteract ultraviolet light damage inflicted by the sun. Despite the efficiency of DNA repair pathways, some forms of endogenous DNA damage still cause mutagenic alterations and may result in human disease.
Topics: DNA Damage; DNA Repair; Humans
PubMed: 8962440
DOI: 10.1098/rstb.1996.0139 -
Mutation Research Aug 2013
Topics: Chromosome Aberrations; DNA Damage; Humans; Risk Factors
PubMed: 23867851
DOI: 10.1016/j.mrgentox.2013.07.002 -
Editorial for the 'Reciprocal Links between RNA Metabolism and DNA Damage' Special Issue: July 2023.Genes Aug 2023Two central parts of molecular biology are the control of genome integrity and genome expression [...].
Two central parts of molecular biology are the control of genome integrity and genome expression [...].
Topics: Molecular Biology; DNA Damage; RNA
PubMed: 37628622
DOI: 10.3390/genes14081570 -
Current Molecular Medicine Mar 2011In recent years there has been intense investigation and rapid progress in our understanding of the cellular responses to various types of endogenous and exogenous DNA... (Review)
Review
In recent years there has been intense investigation and rapid progress in our understanding of the cellular responses to various types of endogenous and exogenous DNA damage that ensure genetic stability. These studies have identified numerous roles for ubiquitylation, the post-translational modification of proteins with single ubiquitin or poly-ubiquitin chains. Initially discovered for its role in targeting proteins for degradation in the proteasome, ubiquitylation functions in a variety of regulatory roles to co-ordinate the recruitment and activity of a large number of protein complexes required for recovery from DNA damage. This includes the identification of essential DNA damage response genes that encode proteins directly involved in the ubiquitylation process itself, proteins that are targets for ubiquitylation, proteins that contain ubiquitin binding domains, as well as proteins involved in the de-ubiquitylation process. This review will focus on the regulatory functions of ubiquitylation in three distinct DNA damage responses that involve ubiquitin modification of proliferating cell nuclear antigen (PCNA) in DNA damage tolerance, the core histone H2A and its variant H2AX in double strand break repair (DSBR) and the Fanconi anaemia (FA) proteins FANCD2 and FANCI in cross link repair.
Topics: Animals; DNA Damage; DNA Repair; Humans; Protein Interaction Domains and Motifs; Protein Structure, Tertiary; Signal Transduction; Ubiquitin; Ubiquitination
PubMed: 21342128
DOI: 10.2174/156652411794859269 -
Molecular Biology Reports Feb 2022Despite commonly use for treatment of type II diabetes, possible effects of glipizide on nuclear transport and DNA damage in cells are unknown. Since clinical response...
BACKGROUND
Despite commonly use for treatment of type II diabetes, possible effects of glipizide on nuclear transport and DNA damage in cells are unknown. Since clinical response of glipizide may change with aging, the aim of the study was to investigate the effect of glipizide by comparing mature and senescent adipocytes.
METHODS AND RESULTS
The effects of glipizide were investigated in 3T3-L1 adipocytes. Effective and lethal doses were determined by real-time monitoring iCELLigence system. Comet assay was performed to determine DNA damage and quantitative PCR was conducted to detect gene expression levels. RAN expressions were found to be up regulated in mature 180 µM glipizide treated adipocytes compared to control group (p < 0.05); whereas down regulated in senescent 180 µM glipizide treated adipocytes compared to their control adipocytes (p < 0.05). Olive Tail Moment values were significantly higher in mature 180 µM glipizide treated adipocytes (MTG) and senescent 180 µM glipizide treated adipocytes (STG) comparing their untreated controls (p < 0.001 and p < 0.001 respectively). Also class 5 comets that shows severe DNA damage were found to be higher in both MTG and STG groups than their controls (p < 0.001 and p < 0.001, respectively). OTM values were higher in STG than MTG (p < 0.001).
CONCLUSIONS
This is the first study that reports glipizide caused DNA damage increasing with senescence in adipocytes. As a response to glipizide treatment Ran gene expression increased in mature; and decreased in senescent adipocytes. Further studies are needed to reveal the effect of glipizide on DNA and nuclear interactions in molecular level.
Topics: 3T3-L1 Cells; Active Transport, Cell Nucleus; Adipocytes; Animals; Cell Differentiation; DNA Damage; Glipizide; Mice
PubMed: 35013863
DOI: 10.1007/s11033-021-06942-5 -
Cell Cycle (Georgetown, Tex.) Jun 2011
Topics: Cell Cycle; Centrioles; Centrosome; DNA Damage
PubMed: 21673504
DOI: 10.4161/cc.10.12.15648 -
Cell Reports Jan 2019We provide a catalog for the effects of the human kinome on cell survival in response to DNA-damaging agents, covering all major DNA repair pathways. By treating 313...
We provide a catalog for the effects of the human kinome on cell survival in response to DNA-damaging agents, covering all major DNA repair pathways. By treating 313 kinase-deficient cell lines with ten diverse DNA-damaging agents, including seven commonly used chemotherapeutics, we identified examples of vulnerability and resistance that are kinase specific. To investigate synthetic lethal interactions, we tested the response to carmustine for 25 cell lines by establishing a phenotypic fluorescence-activated cell sorting (FACS) assay designed to validate gene-drug interactions. We show apoptosis, cell cycle changes, and DNA damage and proliferation after alkylation- or crosslink-induced damage. In addition, we reconstitute the cellular sensitivity of DYRK4, EPHB6, MARK3, and PNCK as a proof of principle for our study. Furthermore, using global phosphoproteomics on cells lacking MARK3, we provide evidence for its role in the DNA damage response. Our data suggest that cancers with inactivating mutations in kinases, including MARK3, are particularly vulnerable to alkylating chemotherapeutic agents.
Topics: DNA Damage; Humans; Signal Transduction
PubMed: 30650350
DOI: 10.1016/j.celrep.2018.12.087 -
Current Alzheimer Research 2016Accumulation of DNA damage and impairment of DNA repair systems are involved in the pathogenesis of different neurodegenerative diseases. Whenever DNA damage is too... (Review)
Review
Accumulation of DNA damage and impairment of DNA repair systems are involved in the pathogenesis of different neurodegenerative diseases. Whenever DNA damage is too extensive, the DNA damage response pathway provides for triggering cellular senescence and/or apoptosis. However, whether the increased level of DNA damage in neurodegenerative disorders is a cause rather than the consequence of neurodegenerative events remains to be established. Among possible DNA lesions, DNA double strand breaks (DSBs) are rare events, nevertheless they are the most lethal form of DNA damage. In neurons, DSBs are particularly deleterious because of their reduced DNA repair capability as compared to proliferating cells. Here, we provide a description of DSB repair systems and describe human studies showing the presence of several types of DNA lesions in three major neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD). Then, we analyze the role of DSB accumulation and deficiency of DSB repair systems in neurodegeneration by examining studies on animal models of neurodegenerative diseases.
Topics: Animals; DNA Breaks, Double-Stranded; DNA Damage; DNA Repair; Disease Models, Animal; Humans; Neurodegenerative Diseases
PubMed: 27033054
DOI: 10.2174/1567205013666160401114915 -
Clinics (Sao Paulo, Brazil) Sep 2018The main goal of chemotherapeutic drugs is to induce massive cell death in tumors. Cisplatin is an antitumor drug widely used to treat several types of cancer. Despite... (Review)
Review
The main goal of chemotherapeutic drugs is to induce massive cell death in tumors. Cisplatin is an antitumor drug widely used to treat several types of cancer. Despite its remarkable efficiency, most tumors show intrinsic or acquired drug resistance. The primary biological target of cisplatin is genomic DNA, and it causes a plethora of DNA lesions that block transcription and replication. These cisplatin-induced DNA lesions strongly induce cell death if they are not properly repaired or processed. To counteract cisplatin-induced DNA damage, cells use an intricate network of mechanisms, including DNA damage repair and translesion synthesis. In this review, we describe how cisplatin-induced DNA lesions are repaired or tolerated by cells and focus on the pivotal role of DNA repair and tolerance mechanisms in tumor resistance to cisplatin. In fact, several recent clinical findings have correlated the tumor cell status of DNA repair/translesion synthesis with patient response to cisplatin treatment. Furthermore, these mechanisms provide interesting targets for pharmacological modulation that can increase the efficiency of cisplatin chemotherapy.
Topics: Antineoplastic Agents; Cisplatin; DNA Damage; DNA Repair; Drug Resistance, Neoplasm; Humans
PubMed: 30208165
DOI: 10.6061/clinics/2018/e478s -
Aging Jun 2014Age‐related DNA damage is regarded as one of the possible explanations of aging. Although a generalized idea about the accumulation of DNA damage with age exists,... (Meta-Analysis)
Meta-Analysis
Age‐related DNA damage is regarded as one of the possible explanations of aging. Although a generalized idea about the accumulation of DNA damage with age exists, results found in the literature are inconsistent. To better understand the question of age‐related DNA damage in humans and to identify possible moderator variables, a metaanalysis was conducted. Electronic databases and bibliographies for studies published since 2004 were searched. Summary odds ratios (ORs) and 95% confidence intervals (CIs) for age‐related DNA damage were calculated in a random‐effects model. A total of 76 correlations from 36 studies with 4676 participants were included. Based on our analysis, a correlation between age and DNA damage was found (r=0.230, p=0.000; 95% confidence interval=0.111‐0.342). The test for heterogeneity of variance indicates that the study´s results are significantly high (Q (75)=1754.831, p=0.000). Moderator variables such as smoking habits, technique used, and the tissue/sample analyzed, are shown to influence age‐related DNA damage (p=0.026; p=0.000; p=0.000, respectively). Nevertheless, sex did not show any influence on this relation (p=0.114). In conclusion, this meta‐analysis showed an association between age and DNA damage in humans. It was also found that smoking habits, the technique used, and tissue/sample analyzed, are important moderator variables in age‐related DNA damage.
Topics: Aging; DNA Damage; Female; Humans; Male
PubMed: 25140379
DOI: 10.18632/aging.100667