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DNA Damage Repair (dna + damage_repair)
Selected AbstractsArsenate and dimethylarsinic acid in drinking water did not affect DNA damage repair in urinary bladder transitional cells or micronuclei in bone marrow,ENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 9 2009Amy Wang Abstract Arsenic is a human skin, lung, and urinary bladder carcinogen, and may act as a cocarcinogen in the skin and urinary bladder. Possible modes of action of arsenic carcinogenesis/cocarcinogenesis include oxidative stress induction and inhibition of DNA damage repair. We investigated the effects of arsenic in drinking water on DNA damage repair in urinary bladder transitional cells and on micronucleus formation in bone marrow. F344 rats were given 100 ppm arsenate [As(V)] or dimethylarsinic acid [DMA(V)] in drinking water for 1 week. The in vivo repair of cyclophosphamide (CP)-induced DNA damage resulting from a single oral gavage of CP, and the in vitro repair of hydrogen peroxide (H2O2)- or formaldehyde-induced DNA damage, resulting from adding H2O2 or formaldehyde into cell medium, were measured by the Comet assay. DMA(V) effects were not observed on either CP-induced DNA damage induction or on DNA repair. Neither DMA(V) nor As(V) increased the H2O2 - or formaldehyde-induced DNA damage, and neither inhibited the repair of H2O2 -induced DNA damage. Neither DMA(V) nor As(V) increased the micronucleus frequency, nor did they elevate micronucleus frequency resulting from CP treatment above the level observed by the treatment with CP alone. These results suggest that arsenic carcinogenesis/cocarcinogenesis in the urinary bladder may not be via DNA damage repair inhibition. To our knowledge this is the first report of arsenic effects on DNA damage repair in the urinary bladder. Environ. Mol. Mutagen. 2009. Published 2009 by Wiley-Liss, Inc. [source] Sister chromatid cohesion: the cohesin cleavage model does not ring trueGENES TO CELLS, Issue 6 2007Vincent Guacci Sister chromatid cohesion is important for high fidelity chromosome segregation during anaphase. Gene products that provide structural components (cohesin complex or cohesin) and regulatory components responsible for cohesion are conserved through eukaryotes. A simple model where cohesion establishment occurs by replication through static cohesin rings and cohesion dissolution occurs by Esp1p/separase mediated cleavage of the cohesin rings (Mcd1p/Rad21p/Scc1p sub-unit cleavage) has become widespread. A growing body of evidence is inconsistent with this ring cleavage model. This review will summarize the evidence showing that cohesin complex is not static but is regulated at multiple cell cycle stages before anaphase in a separase independent manner. Separase is indeed required at anaphase for complete chromosome segregation. However, multiple mechanisms for cohesion dissolution appear to act concurrently during anaphase. Separase is only one such mechanism and its importance varies from organism to organism. The idea that cohesin is a dynamic complex subjected to regulation at various cell cycle stages by multiple mechanisms makes sense in light of the myriad functions in which it has been implicated, such as DNA damage repair, gene silencing and chromosome condensation. [source] Elevated expression of TMEM205, a hypothetical membrane protein, is associated with cisplatin resistanceJOURNAL OF CELLULAR PHYSIOLOGY, Issue 3 2010Ding-Wu Shen Development of cisplatin resistance in cancer cells appears to be a consequence of multiple epigenetic alterations in genes involved in DNA damage repair, proto-oncogenes, apoptosis, transporters, transcription factors, etc. In this study, we found that expression of the hypothetical transmembrane protein TMEM205 (previously known as MBC3205) is associated with cisplatin resistance. TMEM205 was first detected by functional cloning from a retroviral cDNA library made from human cisplatin-resistant (CP-r) cells. TMEM205 is predicted to be a transmembrane protein, but its expression, localization, and function have not previously been investigated. A polyclonal antibody directed to the TMEM205 protein was raised in our laboratory. Using this antibody, it was demonstrated that this protein is located at the cell surface. Its expression is increased in our cisplatin-selected CP-r cell lines, as demonstrated by immunoblotting, confocal examination, and immuno-electron microscopy. Stable transfection of the TMEM205 gene confers resistance to cisplatin by approximately 2.5-fold. Uptake assays with Alexa Fluor-cisplatin showed reduced accumulation in CP-r KB-CP.3 and KB-CP.5 cells, and in TMEM205-transfected cells. Analysis of TMEM205 expression profiles in normal human tissues indicates a differential expression pattern with higher expression levels in the liver, pancreas, and adrenal glands. These results indicate that a novel mechanism for cisplatin resistance is mediated by TMEM205, and also suggest that overexpression of TMEM205 in CP-r cells may be valuable as a biomarker or target in cancer chemotherapy. J. Cell. Physiol. 225: 822,828, 2010. © 2010 Wiley-Liss, Inc. [source] Time-course Expression of DNA Repair-related Genes in Hepatocytes of Zebrafish (Danio rerio) After UV-B ExposurePHOTOCHEMISTRY & PHOTOBIOLOGY, Issue 1 2009Juliana Z. Sandrini The objective of this study was to evaluate the time-course effects of UV-B exposure on expression of genes involved in the DNA repair system of zebrafish (Danio rerio) hepatocytes, a highly competent species in terms of damage repair induced by UV radiation. For gene expression analysis (RT-PCR), cells were exposed to 23.3 mJ cm,2 UV-B, which was the dose that affected viable cell number (reduction of 30% when compared with the control group) and produced no visual alteration on cell morphology. The early response observed (6 h) showed induction in the expression of the CDKI gene (cyclin-dependent kinase inhibitor) and genes related to DNA damage repair (mainly XPC and DDB2), while the late response observed (24 h) was more related to up-regulation of p53 and genes involved in cell cycle arrest (gadd45a, cyclinG1). In all times analyzed, the anti-apoptotic gene Bcl-2 was down-regulated. Another interesting result observed was the up-regulation of the Apex- 1 gene after UV-B exposure, which could indicate the induction of oxidative lesions in the DNA molecule. In conclusion, these results demonstrate an activation of the DNA repair system in hepatocytes of zebrafish exposed to UV-B radiation, mainly involving the participation of p53. [source] Docetaxel,ST1481 sequence exerts a potent cytotoxic activity on hormone-resistant prostate cancer cells by reducing drug resistance-related gene expressionTHE PROSTATE, Issue 2 2010Francesco Fabbri Abstract BACKGROUND The efficacy of current therapy for hormone-refractory prostate cancer is still unsatisfactory and new agents and therapeutic modalities are needed. The aims of the present work were to examine the in vitro activity and mechanisms of action of different antitumor drug combinations in hormone-resistant prostate cancer (HRPC) cell lines. METHODS The activity of docetaxel (Doc), cisplatin (Cis), oxaliplatin (Oxa), SN-38 and ST1481, singly or in combination, was assessed in different HRPC cell lines (PC3, parental DU145 and taxane-resistant DU145-R) by SRB test. Apoptosis was evaluated by TUNEL and ANN-V assays. Extrusion pump activity was studied by Hoechst 33342 assay, while gene expression related to drug efflux mechanisms and DNA damage repair was analyzed by RT-PCR. RESULTS Doc induced a high cytocidal effect in the HRPC cells, whereas Cis, Oxa, SN-38 and ST1481 exerted prevalently cytostatic activity. Doc followed by ST1481 proved to be the most effective drug sequence among those investigated, producing an important synergistic effect (R.I. from 2.0 to 5.2) in all the tested cell lines. Moreover, this sequence induced a significant downregulation of xenobiotic extrusion pump and DNA damage repair gene expression. ST1481 synergistically increased the cytocidal effect of Doc, probably through a downregulation of extrusion pump activity and DNA damage repair-related genes. CONCLUSIONS Our results show that the Doc,,,ST1481 sequence effectively reduces the cancer cell population and restores Doc activity in taxane-resistant HRPC, indicating its potential usefulness as first- or second-line treatment of hormone-refractory prostate cancer. Prostate 70: 219,227, 2010. ©2009 Wiley-Liss, Inc. [source] Purification, crystallization and preliminary X-ray crystallographic studies of the complex between Smc5 and the SUMO E3 ligase Mms21ACTA CRYSTALLOGRAPHICA SECTION F (ELECTRONIC), Issue 8 2009Xinyuan Duan Smc5/6, a protein complex that belongs to the structural maintenance of chromosome (SMC) family, plays a key role in DNA replication, sister chromatid recombination and DNA damage repair. The complex contains eight subunits, including a SUMO E3 ligase Mms21 (Nse2). The activity of Mms21 is important for regulation of Smc5/6 in the response to DNA damage. Mms21 and the Mms21-binding region of Smc5 were overexpressed and purified individually in Escherichia coli with a C-terminal LEHHHHHH tag. The Mms21,Smc5 protein complex was crystallized. The diffraction of the crystals was improved greatly by glutaraldehyde treatment. X-ray diffraction data sets were collected to resolutions of 2.3 and 3.9,Å from native and selenomethionine-derivative protein crystals, respectively. The crystals belonged to space group C2221, with unit-cell parameters a = 47.465, b = 97.574, c = 249.215,Å for the native crystals. [source] Integrated genomic and expression profiling in mantle cell lymphoma: identification of gene-dosage regulated candidate genesBRITISH JOURNAL OF HAEMATOLOGY, Issue 2 2008Margit Schraders Summary Mantle cell lymphoma (MCL) is characterized by the t(11;14)(q13;q32) translocation and several other cytogenetic aberrations, including heterozygous loss of chromosomal arms 1p, 6q, 11q and 13q and/or gains of 3q and 8q. The common intervals of chromosomal imbalance have been narrowed down using array-comparative genomic hybridization (CGH). However, the chromosomal intervals still contain many genes potentially involved in MCL pathogeny. Combined analysis of tiling-resolution array-CGH with gene expression profiling on 11 MCL tumours enabled the identification of genomic alterations and their corresponding gene expression profiles. Only subsets of genes located within given cytogenetic anomaly-intervals showed a concomitant change in mRNA expression level. The genes that showed consistent correlation between DNA copy number and RNA expression levels are likely to be important in MCL pathology. Besides several ,anonymous genes', we also identified various fully annotated genes, whose gene products are involved in cyclic adenosine monophosphate-regulated pathways (PRKACB), DNA damage repair, maintenance of chromosome stability and prevention of rereplication (ATM, ERCC5, FBXO5), energy metabolism (such as genes that are involved in the synthesis of proteins encoded by the mitochondrial genome) and signal transduction (ARHGAP29). Deregulation of these gene products may interfere with the signalling pathways that are involved in MCL tumour development and maintenance. [source] | |||||||||||||