DNA Damage

Source: www.ncbi.nlm.nih.gov --- 13 days ago
Related Articles DNA Damage induced by chronic inflammation contributes to colon carcinogenesis in mice. J Clin Invest. 2008 Jul;118(7):2516-25 Authors: Meira LB, Bugni JM, Green SL, Lee CW, Pang B, Borenshtein D, Rickman BH, Rogers AB, Moroski-Erkul CA, McFaline JL, Schauer DB, Dedon PC, Fox JG, Samson LD Chronic inflammation increases cancer risk. While it is clear that cell signaling elicited by inflammatory cytokines promotes tumor development, the impact of DNA Damage production resulting from inflammation-associated reactive oxygen and nitrogen species (RONS) on tumor development has not been directly tested. RONS induce DNA Damage that can be recognized by alkyladenine DNA glycosylase (Aag) to initiate base excision repair. Using a mouse model of episodic inflammatory bowel disease by repeated administration of dextran sulfate sodium in the drinking water, we show that Aag-mediated DNA repair prevents colonic epithelial Damage and reduces the severity of dextran sulfate sodium-induced colon tumorigenesis. Importantly, DNA base lesions expected to be induced by RONS and recognized by Aag accumulated to higher levels in Aag-deficient animals following stimulation of colonic inflammation. Finally, as a test of the generality of this effect we show that Aag-deficient animals display more severe gastric lesions that are precursors of gastric cancer after chronic infection with Helicobacter pylori. These data demonstrate that the repa ...

Source: www.ncbi.nlm.nih.gov --- 10 days ago
Related Articles Molecular Regulation of DNA Damage-Induced Apoptosis in Neurons of Cerebral Cortex. Cereb Cortex. 2008 Sep 26; Authors: Martin LJ, Liu Z, Pipino J, Chestnut B, Landek MA Cerebral cortical neuron degeneration occurs in brain disorders manifesting throughout life, but the mechanisms are understood poorly. We used cultured embryonic mouse cortical neurons and an in vivo mouse model to study mechanisms of DNA damaged-induced apoptosis in immature and differentiated neurons. p53 drives apoptosis of immature and differentiated cortical neurons through its rapid and prominent activation stimulated by DNA strand breaks induced by topoisomerase-I and -II inhibition. Blocking p53-DNA transactivation with alpha-pifithrin protects immature neurons; blocking p53-mitochondrial functions with mu-pifithrin protects differentiated neurons. Mitochondrial death proteins are upregulated in apoptotic immature and differentiated neurons and have nonredundant proapoptotic functions; Bak is more dominant than Bax in differentiated neurons. p53 phosphorylation is mediated by ataxia telangiectasia mutated (ATM) kinase. ATM inactivation is antiapoptotic, particularly in differentiated neurons, whereas inhibition of c-Abl protects immature neurons but not differentiated neurons. Cell death protein expression patterns in mouse forebrain are mostly similar to cultured neurons. DNA Damage induces prominent p53 activation and apoptosis in cerebral c ...

Source: www.ncbi.nlm.nih.gov --- 39 days ago
Related Articles Low levels of methylmercury induce DNA Damage in rats: protective effects of selenium. Arch Toxicol. 2008 Aug 27; Authors: Grotto D, Barcelos GR, Valentini J, Antunes LM, Angeli JP, Garcia SC, Barbosa F In this study we examined the possible antigenotoxic effect of selenium (Se) in rats chronically exposed to low levels of methylmercury (MeHg) and the association between glutathione peroxidase (GSH-Px) activity and DNA lesions (via comet assay) in the same exposed animals. Rats were divided into six groups as follows: (Group I) received water; (Group II) received MeHg (100 mug/day); (Group III) received Se (2 mg/L drinking water); (Group IV) received Se (6 mg/L drinking water); (Group V) received MeHg (100 mug/day) and Se (2 mg/L drinking water); (Group VI) received MeHg (100 mug/day) and Se (6 mg/L drinking water). Total treatment time was 100 days. GSH-Px activity was determined spectrophotometrically and DNA Damage was determined by comet assay. Mean GSH-Px activity in groups I, II, III, IV, V and VI were, respectively: 40.19 +/- 17.21; 23.63 +/- 6.04; 42.64 +/- 5.70; 38.50 +/- 7.15; 34.54 +/- 6.18 and 41.39 +/- 11.67 nmolNADPH/min/gHb. DNA Damage was represented by a mean score from 0 to 300; the results for groups I, II, III, IV, V and VI were, respectively: 6.87 +/- 3.27; 124.12 +/- 13.74; 10.62 +/- 3.81; 13.25 +/- 1.76; 86.87 +/- 11.95 and 76.25 +/- 7.48. There was a significant inhibition of GSH-Px activity in ...

Source: www.ncbi.nlm.nih.gov --- 23 days ago
Related Articles Repair of deaminated base Damage by Schizosaccharomyces pombe thymine DNA glycosylase. DNA Repair (Amst). 2008 Sep 9; Authors: Dong L, Mi R, Glass RA, Barry JN, Cao W Thymine DNA glycosylases (TDG) in eukaryotic organisms are known for their double-stranded glycosylase activity on guanine/uracil (G/U) base pairs. Schizosaccharomyces pombe (Spo) TDG is a member of the MUG/TDG family that belongs to a uracil DNA glycosylase superfamily. This work investigates the DNA repair activity of Spo TDG on all four deaminated bases: xanthine (X) and oxanine (O) from guanine, hypoxanthine (I) from adenine, and uracil from cytosine. Unexpectedly, Spo TDG exhibits glycosylase activity on all deaminated bases in both double-stranded and single-stranded DNA in the descending order of X>I>U>>O. In comparison, human TDG only excises deaminated bases from G/U and, to a much lower extent, A/U and G/I base pairs. Amino acid substitutions in motifs 1 and 2 of Spo TDG show a significant impact on deaminated base repair activity. The overall mutational effects are characterized by a loss of glycosylase activity on oxanine in all five mutants. L157I in motif 1 and G288M in motif 2 retain xanthine DNA glycosylase (XDG) activity but reduce excision of hypoxanthine and uracil, in particular in C/I, single-stranded hypoxanthine (ss-I), A/U, and single-stranded uracil (ss-U). A proline substitution at I289 in motif 2 causes a significant reduction ...

Source: www.ncbi.nlm.nih.gov --- 36 days ago
Related Articles Lymphocyte DNA Damage and total antioxidant status in patients with white-coat hypertension and sustained hypertension. Turk Kardiyol Dern Ars. 2008;36(4):231-238 Authors: Yıldız A, Gür M, Yılmaz R, Demirbağ R, Celik H, Aslan M, Koçyiğit A OBJECTIVES: We assessed lymphocyte DNA Damage and total antioxidant status (TAS) in patients with white-coat hypertension (WCH) and sustained hypertension (SHT). STUDY DESIGN: The study included 23 patients (14 females, 9 males; mean age 46+/-6 years) with WCH, 21 patients (13 females, 8 males; mean age 45+/-7 years) with newly diagnosed SHT, and 19 age- and sex-matched healthy volunteers as controls. All subjects underwent echocardiographic examination, office blood pressure measurements, and 24-hour ambulatory blood pressure monitoring. DNA Damage was assessed by the alkaline comet assay in peripheral lymphocytes, and plasma TAS levels were determined using an automated measurement method. RESULTS: The two hypertensive groups had similar echocardiographic measurements and office systolic and diastolic blood pressures. The mean daytime and nighttime pressures were significantly higher in the SHT group (p<0.05). Patients with WCH had similar daytime and nighttime pressures compared to the controls (p>0.05). Patients with SHT had significantly increased lymphocyte DNA Damage (p<0.001, for both WCH and control groups) and decreased TAS level (p=0.012 vs WCH group; p<0.001 vs controls). ...

Source: www.moreover.com --- 31 days ago
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Source: www.ncbi.nlm.nih.gov --- 28 days ago
Related Articles Destabilization of DNA duplexes by oxidative Damage at guanine: implications for lesion recognition and repair. J R Soc Interface. 2008 Sep 4; Authors: Jiranusornkul S, Laughton CA We have used molecular dynamics simulations to study the structure and dynamics of a range of DNA duplexes containing the 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapydG) lesion that can result from oxidative Damage at guanine. Compared to the corresponding undamaged DNA duplexes, FapydG-containing duplexes show little gross structural changes-the damaged base remains stacked in to the DNA double helix and retains hydrogen bonds to its cytosine partner. However, the experimentally observed reduction in DNA stability that accompanies lesion formation can be explained by a careful energetic analysis of the simulation data. Irrespective of the nature of the base pairs on either side of the lesion site, conversion of a guanine to a FapydG base results in increased dynamical flexibility in the base (but not in the DNA as a whole) that significantly weakens its hydrogen-bonding interactions. Surprisingly, the stacking interactions with its neighbours are not greatly altered. The formamido group adopts a non-planar conformation that can interact significantly and in a sequence-dependent manner with its 3'-neighbour. We conclude that the recognition of FapydG lesions by the repair protein formamidopyrimidine-DNA glycosylase probably does not in ...

Source: www.ncbi.nlm.nih.gov --- 26 days ago
Related Articles Activation of DNA Damage response signaling in mouse embryonic stem cells. Cell Cycle. 2008 Sep 30;7(18) Authors: Chuykin IA, Lianguzova MS, Pospelova TV, Pospelov VA Mouse embryonic stem cells (mESC) are characterized by high proliferation activity. mESC are highly sensitive to genotoxic stresses and do not undergo G(1)/S checkpoint upon DNA-Damage. mESC are supposed to develop sensitive mechanisms to maintain genomic integrity provided by either DNA Damage repair or elimination of defected cells by apoptosis. The issue of how mESC recognize the damages and execute DNA repair remains to be studied. We analyzed the kinetics of DNA repair foci marked by antibodies to phosphorylated ATM kinase and histone H2AX (gammaH2AX). We showed that mESC display non-induced DNA single-strand breaks (SSBs), as revealed by comet-assay, and a noticeable background of gammaH2AX staining. Exposure of mESC to gamma-irradiation induced the accumulation of phosphorylated ATM-kinase in the nucleus as well as the formation of additional gammaH2AX foci, which disappeared thereafter. To decrease the background of gammaH2AX staining in control non-irradiated cells, we pre-synchronized mESC at the G(2)/M by low concentration of nocodazol for a short time (6 h). The cells were then irradiated and stained for gammaH2AX. Irradiation induced the formation of gammaH2AX foci both in G(2)-phase and mitotic cells, which evidenced for the active state of ...

Source: www.ncbi.nlm.nih.gov --- 39 days ago
Related Articles Necdin regulates p53 acetylation via Sirtuin1 to modulate DNA Damage response in cortical neurons. J Neurosci. 2008 Aug 27;28(35):8772-84 Authors: Hasegawa K, Yoshikawa K Sirtuin1 (Sirt1), a mammalian homolog of yeast Sir2, deacetylates the tumor suppressor protein p53 and attenuates p53-mediated cell death. Necdin, a p53-interacting protein expressed predominantly in postmitotic neurons, is a melanoma antigen family protein that promotes neuronal differentiation and survival. In mammals, the necdin gene (Ndn) is maternally imprinted, and mutant mice carrying mutated paternal Ndn show abnormalities of neuronal development. Here we report that necdin regulates the acetylation status of p53 via Sirt1 to suppress p53-dependent apoptosis in postmitotic neurons. Double-immunostaining analysis demonstrated that necdin colocalizes with Sirt1 in postmitotic neurons of mouse embryonic forebrain in vivo. Coimmunoprecipitation and in vitro binding analyses revealed that necdin interacts with both p53 and Sirt1 to potentiate Sirt1-mediated p53 deacetylation by facilitating their association. Primary cortical neurons prepared from paternal Ndn-deficient mice have high p53 acetylation levels and are sensitive to the DNA-damaging compounds camptothecin and hydrogen peroxide. Moreover, DNA transfection per se increases p53 acetylation and apoptosis in paternal Ndn-deficient neurons, whereas small interfering RNA-mediated p53 knockdown ...

Source: www.ncbi.nlm.nih.gov --- 37 days ago
Related Articles Mechanism of p53 downstream effectors p21 and Gadd45 in DNA Damage surveillance. Sci China C Life Sci. 1999 Aug;42(4):427-34 Authors: Meng X, Dong Y, Sun Z Both p21(WAF1/CIP1) and Gadd45 were activated in a p53-dependent manner in MCF-7 cells after being exposed to ionizing radiation. In order to investigate their roles in DNA Damage suweillance, p21(as)/MCF-7 cells stably transfected by p21 antisense expression plasmid pC-WAF1-AS and Gadd45(as)/MCF-7 stably transfected by Gadd45 antisense expression plasmid pCMVas45 were established. It was observed that G(1) arrest induced by radiation was significantly reduced in Gadd45(as)/MCF-7 cells as well as in p21(as)/MCF7 cells. Repair of radiation damaged report gene greatly reduced in Gadd45(as)/MCF-7 and p21(as)VMCF-7 cells. Apoptosis significantly increased in p21(as)/MCF-7 after exposure to radiation. These results suggest that both p21 and Gadd45 support cellular survival by taking roles in G(1) arrest and DNA repair, furthermore, p21 protects cells from death by inhibiting apoptosis after exposure to ionizing radiation. PMID: 18763134 [PubMed - in process] ...

Source: www.ncbi.nlm.nih.gov --- 22 days ago
Related Articles Effect of somatostatin on repair of ionizing radiation-induced DNA Damage in pituitary adenoma cells GH3. Physiol Res. 2008;57(2):225-35 Authors: Rezácová M, Cáp J, Vokurková D, Lukásová E, Vávrová J, Cerman J, Masín V, Mazánková N Ionizing radiation and somatostatin analogues are used for acromegaly treatment to achieve normalization or reduction of growth hormone hypersecretion and tumor shrinkage. In this study, we investigated a combination of somatostatin (SS14) with ionizing radiation of (60)Co and its effect on reparation of radiation-induced Damage and cell death of somatomammotroph pituitary cells GH3. Doses of gamma-radiation 20-50 Gy were shown to inhibit proliferation and induce apoptosis in GH3 cells regardless of somatostatin presence. It has been found that the D(0) value for GH3 cells was 2.5 Gy. Somatostatin treatment increased radiosensitivity of GH3 cells, so that D(0) value decreased to 2.2 Gy. We detected quick phosphorylation of histone H2A.X upon irradiation by the dose 20 Gy and its colocalization with phosphorylated protein Nbs-1 in the site of double strand break of DNA (DSB). Number of DSB decreased significantly 24 h after irradiation, however, clearly distinguished foci persisted, indicating non repaired DSB, after irradiation alone or after combined treatment by irradiation and SS14. We found that SS14 alone triggers phosphorylation of Nbs1 (p-Nbs1), which correlates with antiproliferativ ...

Source: www.ncbi.nlm.nih.gov --- 7 days ago
Related Articles [Mechanisms for induction of apoptosis in response to DNA Damage] Seikagaku. 2008 Jul;80(7):619-31 Authors: Yoshida K PMID: 18712062 [PubMed - indexed for MEDLINE] ...

Source: www.ncbi.nlm.nih.gov --- 19 days ago
Related Articles American ginseng suppresses inflammation and DNA Damage associated with mouse colitis. Carcinogenesis. 2008 Sep 18; Authors: Jin Y, Kotakadi VS, Ying L, Hofseth AB, Cui X, Wood PA, Windust A, Matesic LE, Pena EA, Chiuzan C, Singh NP, Nagarkatti M, Nagarkatti PS, Wargovich MJ, Hofseth LJ Ulcerative colitis (UC) is a dynamic, idiopathic, chronic inflammatory condition associated with a high colon cancer risk. American ginseng has anti-oxidant properties, and targets many of the players in inflammation. The aim of this study was to test whether American ginseng extract prevents and treats colitis. Colitis in mice was induced by the presence of 1% dextran sulfate sodium (DSS) in the drinking water, or by 1% oxazolone rectally. American ginseng extract was mixed in the chow at levels consistent with that currently consumed by humans as a supplement (75 ppm, equivalent to 58 mg daily). To test prevention of colitis, American ginseng extract was given prior to colitis induction. To test treatment of colitis, American ginseng extract was given after the onset of colitis. In vitro studies were performed to examine mechanisms. Results indicate that American ginseng extract not only prevents, but it treats colitis. iNOS and Cox-2 (markers of inflammation) and p53 (induced by inflammatory stress) are also down-regulated by American ginseng. Mucosal and DNA Damage associated with colitis is at least in part a result of an oxidativ ...

Source: www.ncbi.nlm.nih.gov --- 10 days ago
Related Articles Human semen quality and sperm DNA Damage in relation to urinary metabolites of pyrethroid insecticides. Hum Reprod. 2008 Aug;23(8):1932-40 Authors: Meeker JD, Barr DB, Hauser R BACKGROUND: Exposure to synthetic pyrethroid insecticides is widespread, and is expected to increase among the general population due to the need to replace other common insecticides following regulatory use restrictions. On the basis of limited studies, there is animal and human evidence for altered reproductive or endocrine function following pyrethroid exposure. METHODS: The present study measured urinary pyrethroid metabolites [3-phenoxybenzoic acid (3PBA) and cis- and trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid (CDCCA and TDCCA)], semen quality, sperm motion parameters and sperm DNA Damage with the neutral comet assay in 207 men recruited from an infertility clinic. RESULTS: In multivariate analysis, the highest 3PBA quartile was associated with a suggestive 20.2 million sperm/ml reduction (95% confidence interval -37.1 to + 2.6) in sperm concentration compared with men below the 3PBA median. There were significant inverse associations between TDCCA and sperm motility and sperm motion parameters when adjusting for CDCCA and other covariates. The highest TDCCA quartile was associated with a 15.5% decline (95% confidence interval -26.2 to -4.8) in sperm motility compared with men below the median. In multiple logisti ...

Source: www.ncbi.nlm.nih.gov --- 26 days ago
Related Articles Human MLH1 Protein Participates in Genomic Damage Checkpoint Signaling in Response to DNA Interstrand Crosslinks, while MSH2 Functions in DNA Repair. PLoS Genet. 2008;4(9):e1000189 Authors: Wu Q, Vasquez KM DNA interstrand crosslinks (ICLs) are among the most toxic types of Damage to a cell. For this reason, many ICL-inducing agents are effective therapeutic agents. For example, cisplatin and nitrogen mustards are used for treating cancer and psoralen plus UVA (PUVA) is useful for treating psoriasis. However, repair mechanisms for ICLs in the human genome are not clearly defined. Previously, we have shown that MSH2, the common subunit of the human MutSalpha and MutSbeta mismatch recognition complexes, plays a role in the error-free repair of psoralen ICLs. We hypothesized that MLH1, the common subunit of human MutL complexes, is also involved in the cellular response to psoralen ICLs. Surprisingly, we instead found that MLH1-deficient human cells are more resistant to psoralen ICLs, in contrast to the sensitivity to these lesions displayed by MSH2-deficient cells. Apoptosis was not as efficiently induced by psoralen ICLs in MLH1-deficient cells as in MLH1-proficient cells as determined by caspase-3/7 activity and binding of annexin V. Strikingly, CHK2 phosphorylation was undetectable in MLH1-deficient cells, and phosphorylation of CHK1 was reduced after PUVA treatment, indicating that MLH1 is involved in signaling pso ...

Source: www.ncbi.nlm.nih.gov --- 37 days ago
Related Articles In vivo analysis of PKB/Akt regulation in DNA-PKcs-null mice reveals a role for PKB/Akt in DNA Damage response and tumorigenesis. J Biol Chem. 2008 Aug 29; Authors: Surucu B, Bozulic L, Hynx D, Parcellier A, Hemmings BA Full activation of protein kinase B (PKB/Akt) requires phosphorylation on Thr308 and Ser473. It is well established that Thr308 is phosphorylated by 3-phosphoinositide-dependent kinase-1 (PDK1). Ser473 phosphorylation is mediated by both mTOR/rictor complex (mTORC2) and DNA-dependent protein kinase (DNA-PK) depending on type of stimulus. However, the physiological role of DNA-PK in the regulation of PKB phosphorylation remains to be established. To address this, we analyzed basal, insulin-induced and DNA Damage-induced PKB Ser473 phosphorylation in DNA-PK catalytic subunit-null DNA-PKcs(-/-) mice. Our results revealed that DNA-PK is required for DNA Damage-induced but dispensable for insulin- and growth factor-induced PKB Ser473 phosphorylation. Moreover, DNA-PKcs(-/-) mice showed a tissue-specific increase in basal PKB phosphorylation. In particular, persistent PKB hyperactivity in the thymus apparently contributed to spontaneous lymphomagenesis in DNA-PKcs(-/-) mice. Significantly, these tumors could be prevented by deletion of PKBalpha. These findings reveal stimulus-specific regulation of PKB activation by specific upstream kinases and provide genetic evidence of PKB deregulation in DNA-PKcs(-/-) mic ...

Source: www.ncbi.nlm.nih.gov --- 35 days ago
Related Articles ATM kinase is a master switch for the DeltaNp63alpha phosphorylation/degradation in human head and neck squamous cell carcinoma cells upon DNA Damage. Cell Cycle. 2008 Sep 15;7(18) Authors: Huang Y, Sen T, Nagpal J, Upadhyay S, Trink B, Ratovitski E, Sidransky D We previously found that the pro-apoptotic DNA damaging agent, cisplatin, mediated the proteasome-dependent degradation of DeltaNp63alpha associated with its increased phosphorylated status. Since DeltaNp63alpha usually plays an opposite role to p53 and TAp63 in human cancers, we tested the notion that phosphorylation events induced by DNA Damage would affect the protein degradation of DeltaNp63alpha in HNSCC cells upon cisplatin exposure. We found that DeltaNp63alpha is phosphorylated in the time-dependent fashion at the following positions: S385, T397 and S466, which were surrounded by recognition motifs for ATM, CDK2 and p70s6K kinases, respectively. We showed that chemical agents or siRNA inhibiting the activity of ATM, CDK2 and p70s6K kinases blocked degradation of DeltaNp63alpha in HNSCC cells after cisplatin exposure. Site-specific mutagenesis of DeltaNp63alpha residues targeted for phosphorylation by ATM, CDK2 or p70s6k led to dramatic modulation of DeltaNp63alpha degradation. Finally, we demonstrated that the DeltaNp63alpha protein is a target for direct in vitro phosphorylation by ATM, CDK2 or p70s6K. Our results implicate specific kinases, and target ...

Source: networks.feedburner.com --- 30 days ago
Your DNA samples are precious so take care of them! Here are 5 ways that DNA can be damaged, so now you now what to avoid in the future. ...

Source: www.idahostatesman.com --- 3 days ago
It's that time of year when the leaves turn orange and the offerings on your dinner plate can turn even more vibrant, too. And that's a good thing, because yellow-orange veggies - including carrots, sweet potatoes and winter squash - are great-tasting and chock-full of carotenoids. Why care about carotenoids? These good-for-you nutrients fight the DNA Damage that can make your body old (or sick) before its time. ...