A prevalent cancer susceptibility APOBEC3A hybrid allele bearing APOBEC3B 3′UTR enhances chromosomal DNA damage

Abstract In Aspergillus nidulans, germinating conidia undergo multiple rounds of nuclear division before the formation of the first septum. Previous characterization of temperature-sensitive sepB and sepJ mutations showed that although they block septation, they also cause moderate defects in chromosomal DNA metabolism. Results presented here demonstrate that a variety of other perturbations of chromosomal DNA metabolism also delay septum formation, suggesting that this is a general cellular response to the presence of sublethal DNA damage. Genetic evidence is provided that suggests that high levels of cyclin-dependent kinase (cdk) activity are required for septation in A. nidulans. Consistent with this notion, the inhibition of septum formation triggered by defects in chromosomal DNA metabolism depends upon Tyr-15 phosphorylation of the mitotic cdk p34nimX. Moreover, this response also requires elements of the DNA damage checkpoint pathway. A model is proposed that suggests that the DNA damage checkpoint response represents one of multiple sensory inputs that modulates p34nimX activity to control the timing of septum formation.

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Rad50 Zinc Hook Is Important for the Mre11 Complex to Bind Chromosomal DNA Double-stranded Breaks and Initiate Various DNA Damage Responses

Journal of Biological Chemistry ◽

10.1074/jbc.m112.384750 ◽

2012 ◽

Vol 287 (38) ◽

pp. 31747-31756 ◽

Cited By ~ 22

Author(s):

Jing He ◽

Linda Z. Shi ◽

Lan N. Truong ◽

Chi-Sheng Lu ◽

Niema Razavian ◽

...

Keyword(s):

Dna Damage ◽

Chromosomal Dna ◽

Mre11 Complex ◽

Dna Damage Responses

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DNA Repair: Exploiting the Fanconi Anemia Pathway As a Potential Therapeutic Target

Physiological Research ◽

10.33549/physiolres.932115 ◽

2011 ◽

pp. 453-465 ◽

Cited By ~ 13

Author(s):

T. HUCL ◽

E. GALLMEIER

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Fanconi Anemia ◽

Cancer Susceptibility ◽

Synthetic Lethality ◽

Bone Marrow Failure ◽

Long Term Effects ◽

Alternative Pathways ◽

Repair Mechanisms ◽

Relationship Of

DNA repair is an active cellular process to respond to constant DNA damage caused by metabolic processes and environmental factors. Since the outcome of DNA damage is generally adverse and long term effects may contribute to oncogenesis, cells have developed a variety of DNA repair mechanisms, which operate depending on the type of DNA damage inflicted. At least 15 Fanconi anemia (FA) proteins interact in a common pathway involved in homologous recombination. Inherited homozygous mutations in any of these FA genes cause a rare disease, Fanconi anemia, characterized by congenital abnormalities, progressive bone-marrow failure and cancer susceptibility. Heterozygous germline FA mutations predispose to various types of cancer. In addition, somatic FA mutations have been identified in diverse cancer types. Evidence exists that cells deficient in the FA pathway become dependent on alternative pathways for survival. Additional inhibition of such alternative pathways is thus expected to result in cell death, creating a relationship of synthetic lethality. Identifying these relationships can reveal yet unknown mechanisms of DNA repair and new targets for therapy.

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Cytogenetic Damage of Human Lymphocytes in Humanized Mice Exposed to Neutrons and X Rays 24 h After Exposure

Cytogenetic and Genome Research ◽

10.1159/000516529 ◽

2021 ◽

Vol 161 (6-7) ◽

pp. 352-361

Author(s):

Qi Wang ◽

Younghyun Lee ◽

Monica Pujol-Canadell ◽

Jay R. Perrier ◽

Lubomir Smilenov ◽

...

Keyword(s):

Dna Damage ◽

Radiation Exposure ◽

Human Lymphocytes ◽

Absorbed Dose ◽

Chromosome 1 ◽

X Rays ◽

Chromosomal Dna ◽

Humanized Mouse Model ◽

Significant Difference

Detonation of an improvised nuclear device highlights the need to understand the risk of mixed radiation exposure as prompt radiation exposure could produce significant neutron and gamma exposures. Although the neutron component may be a relatively small percentage of the total absorbed dose, the large relative biological effectiveness (RBE) can induce larger biological DNA damage and cell killing. The objective of this study was to use a hematopoietically humanized mouse model to measure chromosomal DNA damage in human lymphocytes 24 h after in vivo exposure to neutrons (0.3 Gy) and X rays (1 Gy). The human dicentric and cytokinesis-block micronucleus assays were performed to measure chromosomal aberrations in human lymphocytes in vivo from the blood and spleen, respectively. The mBAND assay based on fluorescent in situ hybridization labeling was used to detect neutron-induced chromosome 1 inversions in the blood lymphocytes of the neutron-irradiated mice. Cytogenetics endpoints, dicentrics and micronuclei showed that there was no significant difference in yields between the 2 irradiation types at the doses tested, indicating that neutron-induced chromosomal DNA damage in vivo was more biologically effective (RBE ∼3.3) compared to X rays. The mBAND assay, which is considered a specific biomarker of high-LET neutron exposure, confirmed the presence of clustered DNA damage in the neutron-irradiated mice but not in the X-irradiated mice, 24 h after exposure.

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Dietary sugars and related endogenous advanced glycation end-products increase chromosomal DNA damage in WIL2-NS cells, measured using cytokinesis-block micronucleus cytome assay

Mutagenesis ◽

10.1093/mutage/geaa002 ◽

2020 ◽

Vol 35 (2) ◽

pp. 169-177 ◽

Cited By ~ 3

Author(s):

Permal Deo ◽

Caitlin L McCullough ◽

Theodora Almond ◽

Emma L Jaunay ◽

Leigh Donnellan ◽

...

Keyword(s):

Dna Damage ◽

Advanced Glycation End Products ◽

Chromosomal Dna ◽

Advanced Glycation ◽

Age Related ◽

Genome Damage ◽

Glycation End Products ◽

End Products ◽

High Concentrations

Abstract This study investigated the effect of glucose and fructose, and advanced glycation end-products (AGEs) on genome damage in WIL2-NS cells, measured using the cytokinesis-block micronucleus cytome (CBMN-Cyt) assay. The effect of AGEs was investigated using the bovine serum albumin (AGE-BSA) model system induced either with glucose (Glu–BSA) or with fructose (Fru–BSA). Liquid chromatography-mass spectrometry (LC-MS/MS) analysis showed higher Nε-carboxymethyllysine (CML; 26.76 ± 1.09 nmol/mg BSA) levels in the Glu–BSA model. Nε-Carboxyethyllysine (CEL; 7.87 ± 0.19 nmol/mg BSA) and methylglyoxal-derived hydroimidazolone-1 (MG-H1; 69.77 ± 3.74 nmol/mg BSA) levels were higher in the Fru–BSA model. Genotoxic effects were measured using CBMN-Cyt assay biomarkers [binucleated(BN) cells with micronuclei (MNi), BN with nucleoplasmic bridges (NPBs) and BN with nuclear buds (NBuds)] following 9 days of treatment with either glucose, fructose, Glu–BSA or Fru–BSA. Fructose treatment exerted a significant genotoxic dose–response effect including increases of BN with MNi (R2 = 0.7704; P = 0.0031), BN with NPBs (R2 = 0.9311; P < 0.0001) and BN with NBuds (R2 = 0.7118; P = 0.0091) on cells, whereas the DNA damaging effects of glucose were less evident. High concentrations of AGEs (400–600 µg/ml) induced DNA damage; however, there was no effect on cytotoxicity indices (necrosis and apoptosis). In conclusion, this study demonstrates a potential link between physiologically high concentrations of reducing sugars or AGEs with increased chromosomal damage which is an important emerging aspect of the pathology that may be induced by diabetes. Ultimately, loss of genome integrity could accelerate the rate of ageing and increase the risk of age-related diseases over the long term. These findings indicate the need for further research on the effects of glycation on chromosomal instability and to establish whether this effect is replicated in humans in vivo.

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DNA Damage Regulates Senescence-Associated Extracellular Vesicle Release via the Ceramide Pathway to Prevent Excessive Inflammatory Responses

International Journal of Molecular Sciences ◽

10.3390/ijms21103720 ◽

2020 ◽

Vol 21 (10) ◽

pp. 3720 ◽

Cited By ~ 4

Author(s):

Kazuhiro Hitomi ◽

Ryo Okada ◽

Tze Mun Loo ◽

Kenichi Miyata ◽

Asako J. Nakamura ◽

...

Keyword(s):

Dna Damage ◽

Bacterial Infections ◽

Inflammatory Responses ◽

Extracellular Vesicle ◽

Degradation Pathway ◽

Chromosomal Dna ◽

Sphingomyelin Synthase ◽

Inflammatory Protein ◽

Age Related ◽

Suppressor Mechanism

DNA damage, caused by various oncogenic stresses, can induce cell death or cellular senescence as an important tumor suppressor mechanism. Senescent cells display the features of a senescence-associated secretory phenotype (SASP), secreting inflammatory proteins into surrounding tissues, and contributing to various age-related pathologies. In addition to this inflammatory protein secretion, the release of extracellular vesicles (EVs) is also upregulated in senescent cells. However, the molecular mechanism underlying this phenomenon remains unclear. Here, we show that DNA damage activates the ceramide synthetic pathway, via the downregulation of sphingomyelin synthase 2 (SMS2) and the upregulation of neutral sphingomyelinase 2 (nSMase2), leading to an increase in senescence-associated EV (SA-EV) biogenesis. The EV biogenesis pathway, together with the autophagy-mediated degradation pathway, functions to block apoptosis by removing cytoplasmic DNA fragments derived from chromosomal DNA or bacterial infections. Our data suggest that this SA-EV pathway may play a prominent role in cellular homeostasis, particularly in senescent cells. In summary, DNA damage provokes SA-EV release by activating the ceramide pathway to protect cells from excessive inflammatory responses.

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Mechanistic insight into the role of Poly(ADP-ribosyl)ation in DNA topology modulation and response to DNA damage

Mutagenesis ◽

10.1093/mutage/gez045 ◽

2019 ◽

Vol 35 (1) ◽

pp. 107-118

Author(s):

Bakhyt T Matkarimov ◽

Dmitry O Zharkov ◽

Murat K Saparbaev

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Genotoxic Stress ◽

Strand Break ◽

Dna Supercoiling ◽

Dna Strand Breaks ◽

Chromosomal Dna ◽

Dna Breaks ◽

Strand Breaks ◽

Dna Strand

Abstract Genotoxic stress generates single- and double-strand DNA breaks either through direct damage by reactive oxygen species or as intermediates of DNA repair. Failure to detect and repair DNA strand breaks leads to deleterious consequences such as chromosomal aberrations, genomic instability and cell death. DNA strand breaks disrupt the superhelical state of cellular DNA, which further disturbs the chromatin architecture and gene activity regulation. Proteins from the poly(ADP-ribose) polymerase (PARP) family, such as PARP1 and PARP2, use NAD+ as a substrate to catalyse the synthesis of polymeric chains consisting of ADP-ribose units covalently attached to an acceptor molecule. PARP1 and PARP2 are regarded as DNA damage sensors that, upon activation by strand breaks, poly(ADP-ribosyl)ate themselves and nuclear acceptor proteins. Noteworthy, the regularly branched structure of poly(ADP-ribose) polymer suggests that the mechanism of its synthesis may involve circular movement of PARP1 around the DNA helix, with a branching point in PAR corresponding to one complete 360° turn. We propose that PARP1 stays bound to a DNA strand break end, but rotates around the helix displaced by the growing poly(ADP-ribose) chain, and that this rotation could introduce positive supercoils into damaged chromosomal DNA. This topology modulation would enable nucleosome displacement and chromatin decondensation around the lesion site, facilitating the access of DNA repair proteins or transcription factors. PARP1-mediated DNA supercoiling can be transmitted over long distances, resulting in changes in the high-order chromatin structures. The available structures of PARP1 are consistent with the strand break-induced PAR synthesis as a driving force for PARP1 rotation around the DNA axis.

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Physiological Responses of the Hyperthermophilic Archaeon “Pyrococcus abyssi” to DNA Damage Caused by Ionizing Radiation

Journal of Bacteriology ◽

10.1128/jb.185.13.3958-3961.2003 ◽

2003 ◽

Vol 185 (13) ◽

pp. 3958-3961 ◽

Cited By ~ 26

Author(s):

Edmond Jolivet ◽

Fujihiko Matsunaga ◽

Yoshizumi Ishino ◽

Patrick Forterre ◽

Daniel Prieur ◽

...

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Ionizing Radiation ◽

Dna Synthesis ◽

Gamma Ray ◽

Pyrococcus Furiosus ◽

Repair System ◽

Cell Fractionation ◽

Chromosomal Dna ◽

Pyrococcus Abyssi

ABSTRACT The mechanisms by which hyperthermophilic Archaea, such as “Pyrococcus abyssi” and Pyrococcus furiosus, survive high doses of ionizing gamma irradiation are not thoroughly elucidated. Following gamma-ray irradiation at 2,500 Gy, the restoration of “P. abyssi” chromosomes took place within chromosome fragmentation. DNA synthesis in irradiated “P. abyssi” cells during the DNA repair phase was inhibited in comparison to nonirradiated control cultures, suggesting that DNA damage causes a replication block in this organism. We also found evidence for transient export of damaged DNA out of irradiated “P. abyssi” cells prior to a restart of chromosomal DNA synthesis. Our cell fractionation assays further suggest that “P. abyssi” contains a highly efficient DNA repair system which is continuously ready to repair the DNA damage caused by high temperature and/or ionizing radiation.

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Role of Bacillus subtilis Error Prevention Oxidized Guanine System in Counteracting Hexavalent Chromium-Promoted Oxidative DNA Damage

Applied and Environmental Microbiology ◽

10.1128/aem.01665-14 ◽

2014 ◽

Vol 80 (17) ◽

pp. 5493-5502 ◽

Cited By ~ 6

Author(s):

Fernando Santos-Escobar ◽

J. Félix Gutiérrez-Corona ◽

Mario Pedraza-Reyes

Keyword(s):

Dna Damage ◽

Bacillus Subtilis ◽

Hexavalent Chromium ◽

Oxidative Dna Damage ◽

Chromosomal Dna ◽

Error Prevention ◽

Content Type ◽

Induced Mutagenesis ◽

Oxidized Guanine ◽

Life On Earth

ABSTRACTChromium pollution is potentially detrimental to bacterial soil communities, compromising carbon and nitrogen cycles that are essential for life on earth. It has been proposed that intracellular reduction of hexavalent chromium [Cr(VI)] to trivalent chromium [Cr(III)] may cause bacterial death by a mechanism that involves reactive oxygen species (ROS)-induced DNA damage; the molecular basis of the phenomenon was investigated in this work. Here, we report thatBacillus subtiliscells lacking a functional error prevention oxidized guanine (GO) system were significantly more sensitive to Cr(VI) treatment than cells of the wild-type (WT) strain, suggesting that oxidative damage to DNA is involved in the deleterious effects of the oxyanion. In agreement with this suggestion, Cr(VI) dramatically increased the ROS concentration and induced mutagenesis in a GO-deficientB. subtilisstrain. Alkaline gel electrophoresis (AGE) analysis of chromosomal DNA of WT and ΔGO mutant strains subjected to Cr(VI) treatment revealed that the DNA of the ΔGO strain was more susceptible to DNA glycosylase Fpg attack, suggesting that chromium genotoxicity is associated with 7,8-dihydro-8-oxodeoxyguanosine (8-oxo-G) lesions. In support of this notion, specific monoclonal antibodies detected the accumulation of 8-oxo-G lesions in the chromosomes ofB. subtiliscells subjected to Cr(VI) treatment. We conclude that Cr(VI) promotes mutagenesis and cell death inB. subtilisby a mechanism that involves radical oxygen attack of DNA, generating 8-oxo-G, and that such effects are counteracted by the prevention and repair GO system.

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