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  • 351.
    Renberg-Eriksson, Sara
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Ahlgren-Berg, Alexandra
    DeGrooth, Jeroen
    Haggård-Ljungquist, Elisabeth
    Characterization of the developmental switch region of bacteriophage P2 Hy dis2001In: Virology, ISSN 0042-6822, Vol. 290, no 2, p. 199-210Article in journal (Refereed)
  • 352.
    Renberg-Eriksson, Sara K
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Ahlgren-Berg, Alexandra
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    DeGrooth, Jeroen
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Haggård-Ljungquist, Elisabeth
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Characterization of the developmental switch region of bacteriophage P2 Hy dis.2001In: Virology, ISSN 0042-6822, Vol. 290, no 2, p. 199-210Article in journal (Other academic)
  • 353.
    Renglin, Anna
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Härmälä-Brasken, Ann-Sofi
    Eriksson, John.E
    Önfelt, Agneta
    Mitotic aberrations induced by carbaryl reflect tyrosine kinase inhibition with coincident up-regulation of serine/threonine protein phosphatase activity: implications for coordination of karyokinesis and cytokinesis1999In: Mutagenesis, ISSN 0267-8357, Vol. 14, no 3, p. 327-33.Article in journal (Refereed)
  • 354.
    Renglin, Anna
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Olsson, Anders
    Wachtmeister, Carl Axel
    Önfelt, Agneta
    Mitotic disturbance by carbaryl and the metabolite 1-naphthol may involve kinase-mediated phosphorylation of 1-naphthol to the protein phosphatase inhibitor 1-naphthylphosphate1998In: Mutagenesis, ISSN 0267-8357, Vol. 13, no 4, p. 345-52Article in journal (Refereed)
  • 355.
    Renglin Lindh, A
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Schultz, N
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Saleh-Gohari, N
    Helleday, T
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    RAD51C (RAD51L2) is involved in maintaining centrosome number in mitosis.2007In: Cytogenet Genome Res, ISSN 1424-859X, Vol. 116, no 1-2, p. 38-45Article in journal (Refereed)
  • 356.
    Renglin Lindh, Anna
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Mitotic aberrations in mammalian cells2005Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Almost all cancer cells are aneuploid showing the wrong chromosome number and often with structural aberrations. The degree of aneuploidy correlates with an increase of the severity of the disease and tumour cells with chromosomal instability are more prone to acquire resistance to chemotherapy than other cells. Aneuploidy can arise from mitotic aberrations induced by chemical compounds or genetic defects. The aim of this thesis is to increase the understanding of aneuploidy by investigating mitotic aberrations in mammalian cells.

    Carbaryl is a chemical compound used worldwide as a pesticide substituting DDT. In this study, mammalian cells were cultured and treated with carbaryl or its metabolite 1-naphthol and the resulting aberrant mitotic appearance with cells elongating and cleaving despite displaced and unsegregated choromsomes, were studied. The phosphatase inhibitor 1-naphthyl phosphate was isolated from treated cells and the mitotic pattern caused by carbaryl and 1-napthol was shown to be mimicked by the tyrosine kinase inhibitor tyrphostin. A mechanism for the mitotic pattern is suggested here, involving tyrosine kinase phosphorylation.

    There are repair systems in mammalian cells that repair DNA damage and hence protect cells from aneuploidy. One of these repair pathways is homologous recombination. It has been shown that proteins involved in homologous recombination are defective in cancer cells. Here, mitotic aberrations in cells defect in the recombination repair proteins Rad51C (RAD51L2), XRCC2 and XRCC3 were investigated. For functioning in homologous repair, the XRCC2 and XRCC3 proteins form complexes with RAD51C. Here it was shown that RAD51C deficient cells have aberrant numbers of centrosomes in mitosis, and that cells deficient in XRCC3 have a hampered cytokinesis resulting in binucleated cells.

    There are genetic variations of the XRCC3 protein in humans. The XRCC3 T241M variant has been correlated to increased risk for some cancers. This thesis shows that XRCC3 T241M variant has a mitotic defect resulting in binucleated cells. Furthermore, it is suggested here that despite a functional homologous recombination, the XRCC3 T241M variant is correlated to an increased susceptibility to cancer due to a reduced ability for the cells to enter apoptosis.

    In conclusion, this thesis suggests that mitotic disturbances following treatment with carbaryl is due to interfere with protein phosphorylation. Also, a defect of the Rad51C protein is shown to induce mitotic aberration due to increased centrosome number. The thesis further suggests that the XRCC3 T241M variant may link mitotic aberrations in humans with increased risk for cancer.

  • 357.
    Renglin Lindh, Anna
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Schultz, Niklas
    Rafii, Saeed
    Cox, Angela
    Helleday, Thomas
    Mitotic defect in XRCC3 variant T241M in relation to cancer susceptibilityManuscript (Other academic)
  • 358.
    Renglin Lindh, Anna
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Schultz, Niklas
    Saleh-Gohari, Nasrollah
    Helleday, Thomas
    RAD51C(Rad51L2) is involved in maintaining homologous recombination and centrosome number in mitosisManuscript (Other academic)
  • 359. Resch, Armin
    et al.
    Tedin, Karsten
    Graschopf, Anton
    Haggård-Ljungquist, Elisabeth
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Bläsi, Udo
    Ternary complex formation on leaderless phage mRNA.1995In: FEMS Microbiol Rev, ISSN 0168-6445, Vol. 17, no 1-2, p. 151-7Article in journal (Other academic)
  • 360. Rew, Mary Beth
    et al.
    Robbins, Jooke
    Mattila, David
    Palsböll, Per J.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Berube, Martine
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    How many genetic markers to tag an individual?: An empirical assessment of false matching rates among close relatives2011In: Ecological Applications, ISSN 1051-0761, E-ISSN 1939-5582, Vol. 21, no 3, p. 877-887Article in journal (Refereed)
    Abstract [en]

    Genetic identification of individuals is now commonplace, enabling the application of tagging methods to elusive species or species that cannot be tagged by traditional methods. A key aspect is determining the number of loci required to ensure that different individuals have non-matching multi-locus genotypes. Closely related individuals are of particular concern because of elevated matching probabilities caused by their recent coancestry. This issue may be addressed by increasing the number of loci to a level where full siblings (the relatedness category with the highest matching probability) are expected to have non-matching multi-locus genotypes. However, increasing the number of loci to meet this full-sib criterion greatly increases the laboratory effort, which in turn may increase the genotyping error rate resulting in an upward-biased mark-recapture estimate of abundance as recaptures are missed due to genotyping errors. We assessed the contribution of false matches from close relatives among 425 maternally related humpback whales, each genotyped at 20 microsatellite loci. We observed a very low (0.5-4%) contribution to falsely matching samples from pairs of first-order relatives (i.e., parent and offspring or full siblings). The main contribution to falsely matching individuals from close relatives originated from second-order relatives (e. g., half siblings), which was estimated at; 9%. In our study, the total number of observed matches agreed well with expectations based upon the matching probability estimated for unrelated individuals, suggesting that the full-sib criterion is overly conservative, and would have required a 280% relative increase in effort. We suggest that, under most circumstances, the overall contribution to falsely matching samples from close relatives is likely to be low, and hence applying the full-sib criterion is unnecessary. In those cases where close relatives may present a significant issue, such as unrepresentative sampling, we propose three different genotyping strategies requiring only a modest increase in effort, which will greatly reduce the number of false matches due to the presence of related individuals.

  • 361. Rodriguez, Rene
    et al.
    Hansen, Lasse Tengbjerg
    Phear, Geraldine
    Scorah, Jennifer
    Spang-Thomsen, Mogens
    Cox, Angela
    Helleday, Thomas
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Meuth, Mark
    Thymidine selectively enhances growth suppressive effects of camptothecin/irinotecan in MSI+ cells and tumors containing a mutation of MRE11.2008In: Clin Cancer Res, ISSN 1078-0432, Vol. 14, no 17, p. 5476-83Article in journal (Refereed)
  • 362.
    Romert, Lennart
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Mutagenesis induced by xenobiotics: factors of importance and modification, with special emphasis on glutathione and glutathione transferases1991Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Genetic changes induced by chemical agents can result in cancer. Such tumor formation can be linked to activationof oncogenes, often through specific, definable mutagenic events, e.g., single base-pair mutation in specific codons.

    Most mutagenic and carcinogenic compounds must be activated in order to obtain mutagenic and carcinogenicproperties. This activation can be spontaneous through chemical reactions with other compounds, but is mostfrequently mediated through the action of enzymes. Bioactivated compounds can subsequently be detoxicated throughenzymatic conjugation with hydrophilic biomolecules or, occasionally in spontaneous reactions.

    This thesis deals with certain factors influencing the chain of event resulting in mutagenicity detected in vitro or invivo. Mutagenicity was detected as HPRT mutants in V79 Chinese hamster cells or by the use of the Somatic Mutationand Recombination Test in Drosophila melanogasler. V79 cells, which lack the capacity to bioactivate the modelcompounds studied, were also used as target cells for the detection of mutagenicity in co-cultivation with other cellscompetent in such bioactivation. By the use of this technique, it was possible to investigate factors of importance forbioactivation and detoxication in both primary non-dividing cells, as well as in various established cell lines.

    During this study several model compounds have been used. Compounds that either require metabolic activation toobtain mutagenic properties or that are spontaneously activated. Compounds belonging to the former group werebenzo(a)pyrene (B(a)P), its 7,8-diol and 1,2-dichloroethane (DCE). The latter group was represented byA'-methyl-A'1.nitro-W-nitrososoguanidine (MNNG), V-ethyl-W -nitro-W-nitrososoguanidine (ENNG) and nitrosocimetidine (NC).

    The results obtained are presented in six separate publications. In paper I co-cultivation experiments with alveolarmacrophages (PAMs) show that B(a)P-induced mutagenicity was enhanced 5-10 fold as a consequence of thephagocytic process triggered by the addition of particles. In the study presented in paper II the principal aim was tocompare human PAMs from smokers and non-smokers with respect to their capacity to induce mutations in cocultivatedV79 cells when treated with B(a)P-7,8-diol. No statistical difference between the two groups was detected.

    Papers IV and V deals with the importance of glutathione transferases (GSTs) for the mutagenicity. The resultspresented in paper IV show the protective role of certain GSTs in mutagenesis induced by polycyclic aromatichydrocarbons. However, the results presented in paper V indicate that GSTs can alto participate in bioactivation ofcertain compounds, e.g., DCE.

    In papers III and VI the influence of glutathione and other thiols on the mutagenicity of MNNG, ENNG and NC isinvestigated. These compounds are spontaneously activated by nucleophiles such as thiols. If this activation occursextracellularly, the products also react extracellularly with molecules in the surroundings. Therefore, due to their highreactivity these products are unable to reach the DNA and cause mutations. On the other hand, if this activation occursintracellularly, these compounds are highly mutagenic and the mutagenicity is also dependent on the intracellular levelof thiols.

  • 363. Rosing-Asvid, Aqqalu
    et al.
    Teilmann, Jonas
    Dietz, Rune
    Olsen, Morten Tange
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    First Confirmed Record of Grey Seals in Greenland2010In: Arctic, ISSN 0004-0843, E-ISSN 1923-1245, Vol. 63, no 4, p. 471-473Article in journal (Refereed)
    Abstract [en]

    The presence of grey seals has never before been confirmed in Greenland, but on 30 August 2009 a grey seal was photographed near shore in Southeast Greenland (59 53' N, 43 28' W) The seal was observed within a small group of islands that hosts a harbour seal colony The following day, a seal that might be a young grey seal was photographed at the same location Information from Inuit hunters suggests that grey seals periodically visit Greenland, but the pictures taken in summer 2009 are the first solid proof of this seal species in Greenland

  • 364. Roxström-Lindquist, K
    et al.
    Assefaw-Redda, Yohannes
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Rosikska, K
    Faye, I
    20-hydroxyecdysone indirectly regulates hemolin gene expression in Hyalophora cecropia2005In: Insect molecular biology (Print), ISSN 0962-1075, E-ISSN 1365-2583, Vol. 14, no 6, p. 645-652Article in journal (Refereed)
    Abstract [en]

    Development and innate immune defence are two vital processes that have been demonstrated to use the same or similar molecules and signalling pathways in insects. Hemolin is a moth haemolymph protein belonging to the immunoglobulin superfamily. It is strongly induced upon bacterial infection. However, recent studies indicate a developmental regulation of hemolin. We show that the steroid hormone 20-hydroxyecdysone (20E) can activate the expression of Hyalophora cecropia Hemolin (HcHemolin) in the fat body of diapausing pupae. Using the protein synthesis inhibitor cycloheximide we demonstrate that Hemolin up-regulation by 20E requires ongoing protein synthesis. Moreover, 20E enhances transcription of the Hemolin gene in response to bacteria. Comparing the upstream regions of Manduca sexta Hemolin (MsHemolin) and HcHemolin, we identified four putative regulatory sites. Two are putative hormone response elements (HREs), one with an imperfect inverted repeat (HRE-IR) and one with a monomeric site (HRE-M). An additional monomeric hormone receptor site (MRE) is present only in HcHemolin. The third conserved motif is similar to the interferon (IFN) regulatory factor binding element (IRF-E) and IFN-stimulated response element (ISRE). The fourth conserved element is a κB motif situated between the Cap-site and the TATA-box. Finally, by electrophoresis mobility shift assay we demonstrate that the HRE-IR forms specific complexes with nuclear extract proteins of normal pupae that increase after 20E stimulation.

  • 365.
    Roxström-Lindquist, Katarina
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Terenius, Olle
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Faye, Ingrid
    Stockholm University, Faculty of Humanities. Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Parasite-specific immune response in adult Drosophila melanogaster: a genomic study2004In: EMBO reports, ISSN 1469-221X, Vol. 5, no 2, p. 207-212Article in journal (Refereed)
    Abstract [en]

    Insects of the order Diptera are vectors for parasitic diseases such as malaria, sleeping sickness and leishmania. In the search for genes encoding proteins involved in the antiparasitic response, we have used the protozoan parasite Octosporea muscaedomesticae for oral infections of adult Drosophila melanogaster. To identify parasite-specific response molecules, other flies were exposed to virus, bacteria or fungi in parallel. Analysis of gene expression patterns after 24 h of microbial challenge, using Affymetrix oligonucleotide microarrays, revealed a high degree of microbe specificity. Many serine proteases, key intermediates in the induction of insect immune responses, were uniquely expressed following infection of the different organisms. Several lysozyme genes were induced in response to Octosporea infection, while in other treatments they were not induced or downregulated. This suggests that lysozymes are important in antiparasitic defence.

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  • 366. Saberi, Alihossein
    et al.
    Hochegger, Helfrid
    Szuts, David
    Lan, Li
    Yasui, Akira
    Sale, Julian E
    Taniguchi, Yoshihito
    Murakawa, Yasuhiro
    Zeng, Weihua
    Yokomori, Kyoko
    Helleday, Thomas
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Teraoka, Hirobumi
    Arakawa, Hiroshi
    Buerstedde, Jean-Marie
    Takeda, Shunichi
    RAD18 and poly(ADP-ribose) polymerase independently suppress the access of nonhomologous end joining to double-strand breaks and facilitate homologous recombination-mediated repair.2007In: Mol Cell Biol, ISSN 0270-7306, Vol. 27, no 7, p. 2562-71Article in journal (Refereed)
  • 367.
    Sabri, N
    et al.
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Östlund-Farrants, A-K
    Department of Genetics, Microbiology and Toxicology.
    Hellman, Ulf
    Visa, N
    Department of Molecular Biology and Functional Genomics.
    Evidence for a Posttranscription Role of a TFIIIC-like Protein in Chironomus tentans.2002In: Molecular Biology of the Cell, Vol. 13, p. 1765-1777Article in journal (Refereed)
  • 368.
    Sangsliwan, Traimate
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Haghdoost, Siamak
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    The Nucleotide Pool, a Target for Low-Dose gamma-Ray-Induced Oxidative Stress2008In: Radiation Research, ISSN 0033-7587, E-ISSN 1938-5404, Vol. 170, no 6, p. 776-783Article in journal (Refereed)
    Abstract [en]

    Oxidative stress occurs when the generation of reactive oxygen species (ROS) exceeds the cellular antioxidant capacity. The excess ROS react with and modify cellular components Nucleic acid modifications are of principal interest because they may cause mutations. 8-Oxo-7,8-dihydro-2-deoxyguanosine (8-oxo-dG) is a mutagenic lesion that can be formed by ROS in DNA as well as in the nucleotide pool. 8-Oxo-dG is removed from the DNA by base excision repair and from the nucleotide pool by the nucleotide sanitization enzyme hMTH1. hMTH1 hydrolyzes 8-oxo-dGTP to 8-oxo-dGMP, which is released to the extracellular environment and can serve as a marker of oxidative stress. The aim of this work was to establish the dose-response relationship for radiation-induced extracellular 8-oxo-dG and hMTH1 in the mGy range of gamma rays in three cellular model systems: human whole blood, human fibroblasts and stimulated lymphocytes. Extracellular 8-oxo-dG was analyzed with the use of an ELISA and hMTH 1 by Western blotting. Our results demonstrate that low-dose ionizing radiation induces a stress response that leads to the formation of extracellular 8-oxo-dG and induction of hMTH 1 in all three cellular model systems tested. This suggests that the nucleotide pool is an important target for radiation-induced stress response.

  • 369.
    Sarimov, Ruslan
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Alipov, Eugene D.
    Belyaev, Igory Y.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Fifty Hertz Magnetic Fields Individually Affect Chromatin Conformation in Human Lymphocytes: Dependence on Amplitude, Temperature, and Initial Chromatin State2011In: Bioelectromagnetics, ISSN 0197-8462, E-ISSN 1521-186X, Vol. 32, no 7, p. 570-579Article in journal (Refereed)
    Abstract [en]

    Effects of magnetic field (MF) at 50 Hz on chromatin conformation were studied by the method of anomalous viscosity time dependence (AVTD) in human lymphocytes from two healthy donors. MF within the peak amplitude range of 5-20 mu T affected chromatin conformation. These MF effects differed significantly between studied donors, and depended on magnetic flux density and initial condensation of chromatin. While the initial state of chromatin was rather stable in one donor during one calendar year of measurements, the initial condensation varied significantly in cells from another donor. Both this variation and the MF effect depended on temperature during exposure. Despite these variations, the general rule was that MF condensed the relaxed chromatin and relaxed the condensed chromatin. Thus, in this study we show that individual effects of 50 Hz MF exposure at peak amplitudes within the range of 5-20 mu T may be observed in human lymphocytes in dependence on the initial state of chromatin and temperature. Bioelectromagnetics 32:570-579, 2011.

  • 370.
    Savolainen, Linda
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Transcription Associated Recombination in Mammalian Cells2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    There is increasing evidence that the movement of the transcription machinery through DNA has profound effects on the genomic stability. One such example is a phenomenon known as Transcription Associated Recombination (TAR). Transcription enhances recombination levels to a high degree in all organisms studied, from bacteria to mammals. The underlying causes of the high recombination levels observed are unknown, as are the rationale for the rather riskyhazardous recombination event in this context. Recombination is not a risk-free event; there is e.g. the chancerisk for of loss of heterozygozity, which may eventually lead to tumour formation. So, why is TAR so ubiquitous? This thesis deals with the factors inducing TAR, trying to elucidate the mechanisms catalyzing this event. The proteins involved in executing TAR are unknown in mammals, and one of the aims of this thesis havehas been to investigate the role of well-known DNA repair proteins in TAR. In order to do so, cell lines deficient in crucial DNA repair proteins were stably transfected with a novel recombination construct. Transcription can be controlled over this recombination construct, enabling the detection of transcription associated recombination. We found that TAR is dependent on replication and that inhibition of transcription elongation had no further effect on TAR levels in our system. Further, we found that TAR employs a recombination pathway mechanistically separate from the recombination pathway induced by DNA double strand breaks. This pathway is dependent on BRCA2, a protein required for homologous recombination, but independent of the RAD51 paralog XRCC2. In subsequent studies, we found that the XPD subunit of the combined transcription and repair factor TFIIH is required for TAR, but is dispensable for DNA DSB repair by HR. We went on to investigate the connection between HR repair of UV damages and transcription and found that repair of UV damages requires transcription, but not via the transcription-coupled repair pathway. In conclusion, we found that TAR operates by a recombination pathway separate from DNA double strand break induced recombination. We found a connection with stalled replication, and revealed several of the proteins required for TAR in mammals.

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  • 371.
    Savolainen, Linda
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Cassel, Tobias
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Helleday, Thomas
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    The XPD subunit of TFIIH is required for transcription-associated but not DNA double-strand break-induced recombination in mammalian cells2010In: Mutagenesis, ISSN 0267-8357, E-ISSN 1464-3804, Vol. 25, no 6, p. 623-629Article in journal (Other academic)
    Abstract [en]

    Mutations in the XPD gene can give rise to three phenotypically distinct disorders: xeroderma pigmentosum (XP),  trichothiodystrophy (TTD) or combined XP and Cockayne syndrome (CS) (XP/CS). The role of XPD in nucleotide excision repair explains the increased risk of skin cancer in XP patients, but not all the clinical phenotypes found in XP/CS or TTD patients. Here, we describe that the XPD defective UV5 cell line is impaired in transcription-associated recombination (TAR), which can be reverted by the introduction of the wild type XPD gene expressed from a vector. UV5 cells are defective in TAR, despite having intact transcription and homologous recombination (HR) repair of DNA double-strand breaks (DSBs). Interestingly, we find reduced spontaneous HR in XPD defective cells, suggesting that transcription underlie a portion of spontaneous HR events. We also report that transcription-coupled repair (TCR) defective CSB cells, have a defect in TAR, but not in DSB-induced HR. However, the TAR defect may be associated with a general transcription defect in CSB deficient cells.  In conclusion, we show a novel role for the XPD protein in TAR, linking TAR with TCR.

  • 372.
    Savolainen, Linda
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Helleday, Thomas
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Transcription-associated recombination is independent of XRCC2 and mechanistically separate from homology-directed DNA double-strand break repair2009In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 37, no 2, p. 405-412Article in journal (Refereed)
    Abstract [en]

    It has previously been shown that transcription greatly enhances recombination in mammalian cells. However, the proteins involved in catalysing this process and the recombination pathways involved in transcription-associated recombination (TAR) are still unknown. It is well established that both the BRCA2 protein and the RAD51 paralog protein XRCC2 are required for homologous recombination. Here, we show that the BRCA2 protein is also required for TAR, while the XRCC2 protein is not involved. Expression of the XRCC2 gene in XRCC2 mutated irs1 cells restores the defect in homologous recombination repair of an I-SceI-induced DNA double-strand break, while TAR is unaffected. Interestingly, the XRCC2-deficient irs1 cells are also proficient in recombination induced at slowed replication forks, suggesting that TAR is mechanistically linked with this recombination pathway. In conclusion, we show that TAR depends on BRCA2 but is independent of XRCC2, and that this recombination pathway is separate from that used to repair a two-ended DNA double-strand break.

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  • 373. Scherfer, C.
    et al.
    Wilhelmsson, C.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Loseva, O.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Bidla, G.
    Goto, A.
    Havemann, J.
    Dushay, M. S.
    Theopold, U.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Isolation and Characterization of Hemolymph Clotting Factors in Drosophila melanogaster by a Pullout Method2004In: Current Biology, ISSN 0960-9822, E-ISSN 1879-0445, Vol. 14, p. 625-629Article in journal (Refereed)
  • 374. Schmidt, Otto
    et al.
    Söderhäll, Kenneth
    Theopold, Ulrich
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Faye, Ingrid
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    The Role of Adhesion in Arthropod Immune Recognition2010In: Annual review of entomology, ISSN 1545-2948, Vol. 55, p. 485-504Article in journal (Refereed)
    Abstract [en]

    The recognition and inactivation of toxins and pathogens are mediated by a combination of cell-free and cellular mechanisms. A number of soluble and membrane-bound pattern recognition molecules interact with elicitors to become involved in both cell-free inactivation as well as cellular uptake reactions. Here we describe the possible recognition and effector function of key arthropod immune proteins, such as peroxinectin, hemolin, and hemomucin, as an outcome of changes in adhesiveness, which drive self-assembly reactions leading to cell-free coagulation and cellular uptake reactions. The fact that some of these proteins are essential for immune and developmental functions in some species, but not found in closely related species, may point to the existence of multiprotein assemblies, which are conserved at the mechanistic level and can function with more than one combination of protein constituents. Expected final online publication date for the Annual Review of Entomology Volume 55 is December 03, 2009. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.

  • 375. Segal-Raz, Hava
    et al.
    Mass, Gilad
    Baranes-Bachar, Keren
    Lerenthal, Yaniv
    Wang, Shih-Ya
    Chung, Young Min
    Ziv-Lehrman, Shelly
    Ström, Cecilia E.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Helleday, Thomas
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Hu, Mickey C. -T.
    Chen, David J.
    Shiloh, Yosef
    ATM-mediated phosphorylation of polynucleotide kinase/phosphatase is required for effective DNA double-strand break repair2011In: EMBO Reports, ISSN 1469-221X, E-ISSN 1469-3178, Vol. 12, no 7, p. 713-719Article in journal (Refereed)
    Abstract [en]

    The cellular response to double-strand breaks (DSBs) in DNA is a complex signalling network, mobilized by the nuclear protein kinase ataxia-telangiectasia mutated (ATM), which phosphorylates many factors in the various branches of this network. A main question is how ATM regulates DSB repair. Here, we identify the DNA repair enzyme polynucleotide kinase/phosphatase (PNKP) as an ATM target. PNKP phosphorylates 5'-OH and dephosphorylates 3'-phosphate DNA ends that are formed at DSB termini caused by DNA-damaging agents, thereby regenerating legitimate ends for further processing. We establish that the ATM phosphorylation targets on human PNKP-Ser 114 and Ser 126-are crucial for cellular survival following DSB induction and for effective DSB repair, being essential for damage-induced enhancement of the activity of PNKP and its proper accumulation at the sites of DNA damage. These findings show a direct functional link between ATM and the DSB-repair machinery.

  • 376. Shpanchenko, Olga V.
    et al.
    Golovin, Andrey V.
    Bugaeva, Elizaveta Y.
    Isaksson, Leif A.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Dontsova, Olga A.
    Structural Aspects of trans-Translation2010In: IUBMB Life - A Journal of the International Union of Biochemistry and Molecular Biology, ISSN 1521-6543, E-ISSN 1521-6551, Vol. 62, no 2, p. 120-124Article, review/survey (Refereed)
    Abstract [en]

    trans-Translation is a process which the bacterial cells apply to rescue the ribosomes that are arrested during the translation of damaged mRNA and to get rid of the mRNA and the product polypeptide. In the course of traits-translation, the mRNA-like domain of tmRNA replaces the nonstop messenger RNA bound to the ribosome. Although several structural elements of tmRNA and SmpB known to be essential for correct determination of resume codon, the molecular mechanism of trans-translation is not well understood. Computer modeling has been used to develop a model for the spatial organization of the tmRNA inside the ribosome at different stages of trans-translation leading to a proposal for the mechanism of the template-switching process.

  • 377.
    Sjölinder, Hong
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Jonsson, Ann-Beth
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    In vivo imaging of meningococcal disease dynamics.2012In: Methods in molecular biology (Clifton, N.J.), ISSN 1940-6029, Vol. 799, p. 153-68Article in journal (Refereed)
    Abstract [en]

    Neisseria meningitidis is a human specific organism that causes severe sepsis and/or meningitis with high mortality. The disease scenario is rapid and much remains unknown about the disease process and host-pathogen interaction. In this chapter, we describe a protocol for generating a bioluminescently labeled N. meningitidis strain in order to advance our understanding of meningococcal disease progression. We also describe how in vivo bioluminescence imaging (BLI) can be used to observe novel features of the disease dynamics during meningococcal infection.

  • 378.
    Sjölinder, Hong
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Jonsson, Ann-Beth
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Olfactory nerve--a novel invasion route of Neisseria meningitidis to reach the meninges.2010In: PloS one, ISSN 1932-6203, Vol. 5, no 11, p. e14034-Article in journal (Refereed)
    Abstract [en]

    Neisseria meningitidis is a human-specific pathogen with capacity to cause septic shock and meningitis. It has been hypothesized that invasion of the central nervous system (CNS) is a complication of a bacteremic condition. In this study, we aimed to characterize the invasion route of N. meningitidis to the CNS. Using an intranasally challenged mouse disease model, we found that twenty percent of the mice developed lethal meningitis even though no bacteria could be detected in blood. Upon bacterial infection, epithelial lesions and redistribution of intracellular junction protein N-cadherin were observed at the nasal epithelial mucosa, especially at the olfactory epithelium, which is functionally and anatomically connected to the CNS. Bacteria were detected in the submucosa of the olfactory epithelium, along olfactory nerves in the cribriform plate, at the olfactory bulb and subsequently at the meninges and subarachnoid space. Furthermore, our data suggest that a threshold level of bacteremia is required for the development of meningococcal sepsis. Taken together, N. meningitidis is able to pass directly from nasopharynx to meninges through the olfactory nerve system. This study enhances our understanding how N. meningitidis invades the meninges. The nasal olfactory nerve system may be a novel target for disease prevention that can improve outcome and survival.

  • 379.
    Sjölinder, Hong
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Jonsson, Ann-Beth
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Olfactory Nerve-A Novel Invasion Route of Neisseria meningitidis to Reach the Meninges2010In: PLOS ONE, ISSN 1932-6203, Vol. 5, no 11, p. e14034-Article in journal (Refereed)
    Abstract [en]

    Neisseria meningitidis is a human-specific pathogen with capacity to cause septic shock and meningitis. It has been hypothesized that invasion of the central nervous system (CNS) is a complication of a bacteremic condition. In this study, we aimed to characterize the invasion route of N. meningitidis to the CNS. Using an intranasally challenged mouse disease model, we found that twenty percent of the mice developed lethal meningitis even though no bacteria could be detected in blood. Upon bacterial infection, epithelial lesions and redistribution of intracellular junction protein N-cadherin were observed at the nasal epithelial mucosa, especially at the olfactory epithelium, which is functionally and anatomically connected to the CNS. Bacteria were detected in the submucosa of the olfactory epithelium, along olfactory nerves in the cribriform plate, at the olfactory bulb and subsequently at the meninges and subarachnoid space. Furthermore, our data suggest that a threshold level of bacteremia is required for the development of meningococcal sepsis. Taken together, N. meningitidis is able to pass directly from nasopharynx to meninges through the olfactory nerve system. This study enhances our understanding how N. meningitidis invades the meninges. The nasal olfactory nerve system may be a novel target for disease prevention that can improve outcome and survival.

  • 380.
    Sjölinder, Mikael
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Altenbacher, Georg
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Hagner, Matthias
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Sun, Wei
    Uppsala Univ, Uppsala Biomed Ctr, Dept Med Biochem & Microbiol, Uppsala, Sweden .
    Schedin-Weiss, Sophia
    Uppsala Univ, Uppsala Biomed Ctr, Dept Med Biochem & Microbiol, Uppsala, Sweden .
    Sjölinder, Hong
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Meningococcal Outer Membrane Protein NhhA Triggers Apoptosis in Macrophages.2012In: PloS one, ISSN 1932-6203, Vol. 7, no 1, p. e29586-Article in journal (Refereed)
    Abstract [en]

    Phagocytotic cells play a fundamental role in the defense against bacterial pathogens. One mechanism whereby bacteria evade phagocytosis is to produce factors that trigger apoptosis. Here we identify for the first time a meningococcal protein capable of inducing macrophage apoptosis. The conserved meningococcal outer membrane protein NhhA (Neisseria hia/hsf homologue A, also known as Hsf) mediates bacterial adhesion and interacts with extracellular matrix components heparan sulphate and laminin. Meningococci lacking NhhA fail to colonise nasal mucosa in a mouse model of meningococcal disease. We found that exposure of macrophages to NhhA resulted in a highly increased rate of apoptosis that proceeded through caspase activation. Exposure of macrophages to NhhA also led to iNOS induction and nitric oxide production. However, neither nitric oxide production nor TNF-α signaling was found to be a prerequisite for NhhA-induced apoptosis. Macrophages exposed to wildtype NhhA-expressing meningococci were also found to undergo apoptosis whereas NhhA-deficient meningococci had a markedly decreased capacity to induce macrophage apoptosis. These data provide new insights on the role of NhhA in meningococcal disease. NhhA-induced macrophage apoptosis could be a mechanism whereby meningococci evade immunoregulatory and phagocytotic actions of macrophages.

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  • 381.
    Sjölinder, Mikael
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Altenbacher, Georg
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Wang, Xiao
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Gao, Yumin
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Hansson, Charlotta
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Sjölinder, Hong
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    The Meningococcal Adhesin NhhA Provokes Proinflammatory Responses in Macrophages via Toll-Like Receptor 4-Dependent and -Independent Pathways2012In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 80, no 11, p. 4027-4033Article in journal (Refereed)
    Abstract [en]

    Activation of macrophages by Toll-like receptors (TLRs) and functionally related proteins is essential for host defense and innate immunity. TLRs recognize a wide variety of pathogen-associated molecules. Here, we demonstrate that the meningococcal outer membrane protein NhhA has immunostimulatory functions and triggers release of proinflammatory cytokines from macrophages. NhhA-induced cytokine release was found to proceed via two distinct pathways in RAW 264.7 macrophages. Interleukin-6 (IL-6) secretion was dependent on activation of TLR4 and required the TLR signaling adaptor protein MyD88. In contrast, release of tumor necrosis factor (TNF) was TLR4 and MyD88 independent. Both pathways involved NF-kappa B-dependent gene regulation. Using a PCR-based screen, we could identify additional targets of NhhA-dependent gene activation such as the cytokines and growth factors IL-1 alpha, IL-1 beta, granulocyte colony-stimulating factor (G-CSF), and granulocyte-macrophage colony-stimulating factor (GM-CSF). In human monocyte-derived macrophages, G-CSF, GM-CSF, and IL-6 were found to be major targets of NhhA-dependent gene regulation. NhhA induced transcription of IL-6 and G-CSF mRNA via TLR4-dependent pathways, whereas GM-CSF transcription was induced via TLR4-independent pathways. These data provide new insights into the role of NhhA in host-pathogen interaction.

  • 382. Skaug, H. J.
    et al.
    Berube, Martine
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Palsboll, P. J.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Detecting dyads of related individuals in large collections of DNA-profiles by controlling the false discovery rate2010In: MOL ECOL RESOUR, ISSN 1755-098X, Vol. 10, no 4, p. 693-700Article in journal (Refereed)
    Abstract [en]

    The search for pairs (dyads) of related individuals in large databases of DNA-profiles has become an increasingly important inference tool in ecology. However, the many, partly dependent, pairwise comparisons introduce statistical issues. We show that the false discovery rate (FDR) procedure is well suited to control for the proportion of false positives, i.e. dyads consisting of unrelated individuals, which under normal circumstances would have been labelled as related individuals. We verify the behaviour of the standard FDR procedure by simulation, demonstrating that the FDR procedure works satisfactory in spite of the many dependent pairwise comparisons involved in an exhaustive database screening. A computer program that implements this method is available online. In addition, we propose to implement a second stage in the procedure, in which additional independent genetic markers are used to identify the false positives. We demonstrate the application of the approach in an analysis of a DNA database consisting of 3300 individual minke whales (Balaenoptera acutorostrata) each typed at ten microsatellite loci. Applying the standard procedure with an FDR of 50% led to the identification of 74 putative dyads of 1st- or 2nd-order relatives. However, introducing the second step, which involved additional genotypes at 15 microsatellite loci, revealed that only 21 of the putative dyads can be claimed with high certainty to be true dyads.

  • 383.
    Skiöld, Sara
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Endogenous stress responses as a marker for individual radiation sensitivity2011Licentiate thesis, monograph (Other academic)
  • 384. Sleeth, Kate M
    et al.
    Sørensen, Claus Storgaard
    Issaeva, Natalia
    Dziegielewski, Jaroslaw
    Bartek, Jiri
    Helleday, Thomas
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    RPA mediates recombination repair during replication stress and is displaced from DNA by checkpoint signalling in human cells.2007In: J Mol Biol, ISSN 0022-2836, Vol. 373, no 1, p. 38-47Article in journal (Refereed)
  • 385. Somaiah, Navita
    et al.
    Yarnold, John
    Lagerqvist, Anne
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Rothkamm, Kai
    Helleday, Thomas
    Homologous recombination mediates cellular resistance and fraction size sensitivity to radiation therapy2013In: Radiotherapy and Oncology, ISSN 0167-8140, E-ISSN 1879-0887, Vol. 108, no 1, p. 155-161Article in journal (Refereed)
    Abstract [en]

    Purpose: Cellular sensitivity to radiotherapy total dose and fraction size is strongly influenced by DNA double strand break (DSB) repair. Here, we investigate response to radiotherapy fraction size using CHO cell lines deficient in specific DNA repair pathways in response to radiation induced DNA double strand breaks (DSB). Experimental design: We irradiated CHO cell lines, AA8 (WT), irs1SF (XRCO-), V3-3 (DNA-PKcs-) and EM9 (XRCC1-) with 16 Gy in 1 Gy daily fractions over 3 weeks or 16 Gy in 4 Gy daily fractions over 4 days, and studied clonogenic survival, DNA DSB repair kinetics (RAD51 and 53BP1 foci staining) and cell cycle profiles (flow cytometry). Results: In response to fractionated radiotherapy, wild-type and DNA repair defective cells accumulated in late S/G2 phase. In cells proficient in homologous recombination (HR), accumulation in S/G2 resulted in reduced sensitivity to fraction size and increased cellular resistance (clonogenic survival). Sensitivity to fraction size was also lost in NHEJ-defective V3-3 cells, which likely rely on functional HR. By contrast, HR-defective irs1SF cells, with functional NHEJ, remained equally sensitive to fractionation throughout the 3-week treatment. Conclusions: The high fidelity of HR, which is independent of induced DNA damage level, is postulated to explain the low fractionation sensitivity and cellular resistance of cells in S/G2 phase. In conclusion, our results suggest that HR mediates resistance to fractionated radiotherapy, an observation that may help future efforts to improve radiotherapy outcome.

  • 386.
    Staaf, Elina
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Cellular effects after exposure to mixed beams of ionizing radiation2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Mixed beams of ionizing radiation in our environment originate from space, the bedrock and our own houses. Radiotherapy patients treated with boron neutron capture therapy or with high energy photons are also exposed to mixed beams of gamma radiation and neutrons. Earlier investigations have reported additivity as well as synergism (a greater than additive response) when combining radiations of different linear energy transfer. However, the outcome seemed to be dependent on the experimental setup, especially the order of irradiation and the temperature at exposure.

    A unique facility allowing simultaneously exposure of cells to X-rays and 241Am alpha particles at 37 ºC was constructed and characterized at the Stockholm University (Paper I). To investigate the cytogenetic response to mixed beam irradiation (graded doses of alpha particles, X-rays or a mixture of both) several different cell types were utilized. AA8 Chinese Hamster Ovary cells were analyzed for clonogenic survival (Paper I), human peripheral blood lymphocytes were analyzed for micronuclei and chromosomal aberrations (Paper II and Paper III respectively) and VH10 normal human fibroblasts were scored for gamma-H2AX foci (Paper IV).

    For clonogenic survival, mixed beam results were additive, while a significant synergistic effect was observed for micronuclei and chromosomal aberrations. The micronuclei dose responses were linear, and a significant synergistic effect was present at all investigated doses. From the analysis of micronuclei distributions we speculated that the synergistic effect was due to an impaired repair of X-ray induced DNA damage, a conclusion that was supported by chromosomal aberration results. Gamma-H2AX foci dose responses were additive 1 h after exposure, but the kinetics indicated that the presence of low LET-induced damage engages the DNA repair machinery, leading to a delayed repair of the more complex DNA damage induced by alpha particles. These conclusions are not necessary contradictory since fast repair does not necessarily equal correct repair. Taken together, the observed synergistic effects indicate that the risks of stochastic effects from mixed beam exposure may be higher than expected from adding the individual dose components.

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  • 387.
    Staaf, Elina
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    DNA damage and repair in cells exposed to mixed beams of radiation.2010Licentiate thesis, monograph (Other academic)
  • 388.
    Staaf, Elina
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Brehwens, Karl
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Haghdoost, Siamak
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Czub, Joanna
    Institute of Physics, Jan Kochanowski University, Kielce, Poland.
    Wojcik, Andrzej
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Gamma-H2AX foci in cells exposed to a mixed beam of X-rays and alpha particlesManuscript (preprint) (Other academic)
  • 389.
    Staaf, Elina
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Brehwens, Karl
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Haghdoost, Siamak
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Nievaart, Sander
    Pachnerova-Brabcova, Katerina
    Czub, Joanna
    Braziewicz, Janusz
    Wojcik, Andrzej
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology. Jan Kochanowski University, Poland.
    Micronuclei in human peripheral blood lymphocytes exposed to mixed beams of X-rays and alpha particles2012In: Radiation and Environmental Biophysics, ISSN 0301-634X, E-ISSN 1432-2099, Vol. 51, no 3, p. 283-293Article in journal (Refereed)
    Abstract [en]

    The purpose of this study was to analyse the cytogenetic effect of exposing human peripheral blood lymphocytes (PBL) to a mixed beam of alpha particles and X-rays. Whole blood collected from one donor was exposed to different doses of alpha particles ((241)Am), X-rays and a combination of both. All exposures were carried out at 37 °C. Three independent experiments were performed. Micronuclei (MN) in binucleated PBL were scored as the endpoint. Moreover, the size of MN was measured. The results show that exposure of PBL to a mixed beam of high and low linear energy transfer radiation led to significantly higher than expected frequencies of MN. The measurement of MN size did not reveal any differences between the effect of alpha particles and mixed beam. In conclusion, a combined exposure of PBL to alpha particles and X-rays leads to a synergistic effect as measured by the frequency of MN. From the analysis of MN distributions, we conclude that the increase was due to an impaired repair of X-ray-induced DNA damage.

  • 390.
    Staaf, Elina
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Brehwens, Karl
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Haghdoost, Siamak
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Pachnerova-Brabcova, Katerina
    Czub, Joanna
    Braziewicz, Janusz
    Nievaart, Sander
    Wojcik, Andrzej
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Characterisation of a setup for mixed beam exposures of cells to Am-241 alpha particles and X-rays2012In: Radiation Protection Dosimetry, ISSN 0144-8420, E-ISSN 1742-3406, Vol. 151, no 3, p. 570-579Article in journal (Refereed)
    Abstract [en]

    Exposure of humans to mixed fields of high- and low-linear energy transfer (LET) radiation occurs in many situations—for example, in urban areas with high levels of indoor radon as well as background gamma radiation, during airplane flights or certain forms of radiation therapy. From the perspective of health risk associated with exposure to mixed fields, it is important to understand the interactions between different radiation types. In most cellular investigations on mixed beams, two types of irradiations have been applied sequentially. Simultaneous irradiation is the desirable scenario but requires a dedicated irradiation facility. The authors have constructed a facility where cells can be simultaneously exposed to 241Am alpha particles and 190-kV X-rays at 37°C. This study presents the technical details and the dosimetry of the setup, as well as validates the performance of the setup for clonogenic survival in AA8 Chinese hamster ovary cells. No significant synergistic effect was observed. The relative biological effectiveness of the alpha particles was 2.56 for 37 % and 1.90 for 10 % clonogenic survival.

  • 391.
    Staaf, Elina
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Deperas-Kaminska, Marta
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Brehwens, Karl
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Haghdoost, Siamak
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Czub, Joanna
    Jan Kochanowski University, Kielce, Poland.
    Wojcik, Andrzej
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Higher than expected frequencies of complex aberrations in lymphocytes exposed to mixed beams of 241Am alpha particles and X-raysManuscript (preprint) (Other academic)
  • 392.
    Stancek, Martin
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Translational accuracy, ribozyme efficiency and NAD metabolism in Escherichia coli2004Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Interactions between the translational machinery and mRNA in Escherichia coli have been studied. In the first section nonsense codon readthrough and changed translational reading frame were measured in different growth phases. In early exponential phase, about 7% of –1 frameshift at a U9 slippery sequence is detectable; upon entry into stationary phase this frameshifting increases to about 40% followed by a decrease in stationary phase. A similar increase is observed in the case of +1 reading frameshift at the U9 sequence, which increases from 13% early exponential phase up to 38% at the beginning of stationary phase followed by a decrease. The level of readthrough decreases upon entry into stationary phase. Thus, the levels of both stop codon readthrough and frameshifting are growth phase dependent, though not in an identical fashion.

    The second section is focused on the interaction between a cis-cleaving hammerhead ribozyme (Rz) in an mRNA and a translating ribosome in vivo. It is shown that one of the semi-active constructs can be used as an indicator for ribosomes that read through or terminate at a stop codon upstream of the Rz sequence in the mRNA.

    A temperature sensitive mutant, 72c, is analyzed in the third section. The mutant shows a pleoitropic phenotype that indicates disturbances in the transcription or the translation apparatus. The mutation fusB was identified as a frameshift mutation in a nadD gene and renamed nadD72. The gene codes for a nicotinic acid adenylyltransferase (NAMNAT). The analysis of intracellular nucleotide pools showed that very little NAD is produced at the permissive temperature and no synthesis is observed at non-permissive temperature. It was concluded that a small decrease in NAD levels affects ability to grow on minimal medium at 42°C and a large decrease causes a more pleiotropic phenotype. The enzyme was analyzed further; several residues in the active site and at the C-terminus were mutated in an effort to better characterize their roles in catalysis. The data for the C-terminus were not conclusive but amino acid residues His-45, Arg-46 and Thr-11 could be assigned to the active site.

  • 393.
    Stancek, Martin
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Schnell, Robert
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Rydén-Aulin, Monica
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Analysis of Escherichia coli nicotinate mononucleotide adenylyltransferase mutants in vivo and in vitro.2005In: BMC Biochem, ISSN 1471-2091, Vol. 6, p. 16-Article in journal (Other academic)
  • 394.
    Stenström, Magnus
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Regulation of gene expression by translation initiation efficiency in E. coli2001Doctoral thesis, comprehensive summary (Other academic)
  • 395.
    Stockenberg, Anne
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    The role of sediments in nitrogen cycling in the larger Baltic Sea1998Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The eutrophication of coastal areas has become a widespread problem over the last decades. In the Baltic Sea, the input of nitrogen and phosphorus has increased by four and eight times, respectively, since the turn of the century, and this is considered the direct cause of the eutrophication of this ecosystem. Given that nitrogen is the main limiting nutrient for primary production in the Baltic, it is imperative to understand the dynamics of the cycling of this nutrient. Sediments play an important role in this cycle, and may act as either a sink or a source of nitrogen to the water column. This thesis has investigated the role of Baltic sediments in nitrogen cycling.

    Measurements of nutrient fluxes over the sediment-water interface have been performed in laboratory incubations of sediment cores. In addition, direct measurements of the bacterial denitrification process, which removes nitrogen from the aquatic ecosystem, have also been conducted in sediment cores. All measurements have been made with some spatial, temporal and ecosystem variation. Furthermore, a manipulative experiment investigating the effect of added algal material on sediment mineralisation processes has been carried out.

    It was seen that Baltic sediments are not an important source of nitrogen to the water column. The net release of inorganic nitrogen could support 0-7.4% of phytoplankton nitrogen demand. Net release of inorganic phosphorus was more variable, and could under certain conditions supply >100% of the phytoplankton phosphorus demand. Denitrification rates were comparatively low, mostly <30 (mol N m-2 h-1, and would remove around 30% of the total anthropogenic nitrogen input to the water column. It is suggested that diffusion of nitrate to the site of denitrification is the ultimate controlling factor of denitrification activity. Further, calculations showed that burial of nitrogen may be equally important as denitrification in nitrogen removal in the Baltic.

  • 396.
    Stoimenov, Ivaylo
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Interplay between Transcription and Homologous Recombination in the Presence of DNA Damage2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The biochemical processes of DNA repair, replication and recombination compete for the same substrate, the DNA molecule. This competition is natural, as each process requires the same template. In order to resolve possible conflicts between these processes, when they take place on a particular stretch of DNA, certain crosstalk is expected. The complexity is additionally increased by the existence of another DNA dependent process, which occurs in all phases of the cell cycle: transcription.

    This thesis aims to investigate the link between transcription inhibition and homologous recombination, especially in the context of UV-induced DNA damage. The results show that the transcription inhibitor 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB) induces homologous recombination. The DNA damage caused by UVC irradiation is repaired mainly via nucleotide excision repair, however, it is also known to trigger recombinational repair. In the presence of UV-induced damage, transcription inhibition by DRB potentiates the induction of homologous recombination as a necessary mechanism of cell survival.

    The thesis also focuses on the toxicity mechanisms of the chemotherapeutic compound 6-thioguanine (6TG). The work in the thesis suggests application of 6TG as a treatment for hereditary forms of breast cancer, with genetically altered BRCA1 or BRCA2 functions. Most importantly, the treatment with 6TG is applicable to breast cancers, which have developed resistance to another class of chemotherapeutic drugs, poly-(ADP-ribose) polymerase (PARP) inhibitors. Repair of the DNA damage induced by 6TG treatment is investigated further with a particular focus the pathway of DNA damage avoidance involving DNA polymerase η. The function of DNA polymerase η seems to be an important factor for the outcome of DNA repair after 6TG exposure. The deficiency of DNA polymerase η is also investigated in connection with normal replication and the repair of UV-induced DNA damage.

    In summary, the work in the thesis sheds more light onto the fundamental connections between DNA replication, recombination, transcription, repair and damage avoidance. On a more practical side, the information obtained about these fundamental connections is used to suggest a possible therapy for several forms of breast cancer.

  • 397.
    Stoimenov, Ivaylo
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Elvers, Ingegerd
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Helleday, Thomas
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Polymerase η proficiency sensitises cells to 6-thioguanineManuscript (preprint) (Other academic)
    Abstract [en]

    Severe photosensitivity of the skin and predisposition to cancer development are two important features whichcharacterising a genetic syndrome known as Xeroderma pigmentosum. An interesting class of patients has beendescribed, characterised by a proficiency in nucleotide excision repair and a defect in the DNA damage avoidancepathways. This class is termed Xeroderma pigmentosum variant (XP-V) and is known to be caused by a deficiencyin the function of the specific DNA Polymerase η. Cells derived from XP-V patients are sensitivie not only to UVlight but also to crosslinkers such as cisplatin, and Polη overexpression is potentially relevant to development ofcisplatin resistance. In this paper we investigate the importance of the Polη status in the response to treatment withthe chemotherapeutic agent 6-thioguanine (6TG). Our results show that Polη deficient cells are more resistant totreatment with 6TG in comparison to Polη complemented cells. This is in contrast to the typical UV sensitivity ofPolη deficient cells, which is confirmed in the same cells. We also show that 6TG has a growth retardation effect,regardless of the Polη status. There were no DNA double-strand breaks detected in a short period after theexposure to 6TG in physiologically relevant doses, although a DNA damage response was observed in high doses.It was previously demonstrated that 6TG can be used to kill cisplatin resistant cells and these data may indicateone potential explanation.

  • 398.
    Stoimenov, Ivaylo
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Gottipai, Ponnari
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Savolainen, Linda
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Niklas, Schultz
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Helleday, Thomas
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Transcription-associated UV-induced DNA damage triggers futile homologous recombination repair in mammalian cellsManuscript (preprint) (Other academic)
  • 399.
    Stoimenov, Ivaylo
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Gottipati, Ponnari
    Schultz, Niklas
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Helleday, Thomas
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Transcription inhibition by 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB) causes DNA damage and triggers homologous recombination repair in mammalian cells2011In: Mutation research, ISSN 0027-5107, E-ISSN 1873-135X, Vol. 706, no 1-2, p. 1-6Article in journal (Refereed)
    Abstract [en]

    Transcription, replication and homologous recombination are intrinsically connected and it is well established that an increase of transcription is associated with an increase in homologous recombination. Here, we have studied how homologous recombination is affected during transcription inhibition by 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB), a compound that prevents activating phosphorylations of the RNA Pol II C-terminal domain. We identify that DRB triggers an increase in homologous recombination within the hprt gene as well as increasing RAD51 foci formation in mammalian cells. Furthermore, we find that DRB-induced transcriptional stress is associated with formation of the nuclear foci of the phosphorylated form of H2AX (γH2AX). We accounted that about 72% of RAD51 foci co-localized with the observed γH2AX foci. Interestingly, we find that XRCC3 mutated, homologous recombination defective cells are hypersensitive to the toxic effect of DRB and fail to form RAD51 foci. In conclusion, we show that DRB-induced transcription inhibition is associated with the formation of a lesion that triggers RAD51-dependent homologous recombination repair, required for survival under transcriptional stress.

  • 400.
    Stoimenov, Ivaylo
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Helleday, Thomas
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    PCNA on the crossroad of cancer.2009In: Biochemical Society transactions, ISSN 1470-8752, Vol. 37, no Pt 3, p. 605-13Article in journal (Refereed)
    Abstract [en]

    Cancer is caused by genetic changes that often arise following failure to accurately replicate the DNA. PCNA (proliferating-cell nuclear antigen) forms a ring around the DNA to facilitate and control DNA replication. Emerging evidence suggests that PCNA is at the very heart of many essential cellular processes, such as DNA replication, repair of DNA damage, chromatin structure maintenance, chromosome segregation and cell-cycle progression. Progression of the DNA replication forks can be blocked by DNA lesions, formed either by endogenous damage or by exogenous agents, for instance anticancer drugs. Cellular response often results in change of PCNA function triggered either by specific post-translational modification of PCNA (i.e. ubiquitylation) or by exchange of its interaction partners. This puts PCNA in a central position in determining the fate of the replication fork. In the present article, we review PCNA modifications and interaction partners, and how those influence the course of events at replication forks, which ultimately determines both tumour progression as well as the outcome of anticancer treatment.

5678910 351 - 400 of 476
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