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  • 151. Matsuoka, Atsuko
    et al.
    Lundin, Cecilia
    Johansson, Fredrik
    Sahlin, Margareta
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Fukuhara, Kiyoshi
    Sjöberg, Britt-Marie
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Jenssen, Dag
    Önfelt, Agneta
    Correlation of sister chromatid exchange formation through homologous recombination with ribonucleotide reductase inhibition.2004In: Mutat Res, ISSN 0027-5107, Vol. 547, no 1-2, p. 101-7Article in journal (Other academic)
    Abstract [en]

    We conducted the recombination and sister chromatid exchange (SCE) assays with five chemicals (hydroxyurea (HU), resveratrol, 4-hydroxy-trans-stilbene, 3-hydroxy-trans-stilbene, and mitomycin C) in Chinese hamster cell line SPD8/V79 to confirm directly that SCE is a result of homologous recombination (HR). SPD8 has a partial duplication in exon 7 of the endogenous hprt gene and can revert to wild type by homologous recombination. All chemicals were positive in both assays except for 3-hydroxy-trans-stilbene, which was negative in both. HU, resveratrol, and 4-hydroxy-trans-stilbene were scavengers of the tyrosyl free radical of the R2 subunit of mammalian ribonucleotide reductase. Tyrosyl free radical scavengers disturb normal DNA replication, causing replication fork arrest. Mitomycin C is a DNA cross-linking agent that also causes replication fork arrest. The present study suggests that replication fork arrest, which is similar to the early phases of HR, leads to a high frequency of recombination, resulting in SCEs. The findings show that SCE may be mediated by HR.

  • 152. McLaughlin, Paul J.
    et al.
    Keegan, Liam P.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics. University of Edinburgh, UK.
    Conflict RNA modification, host-parasite co-evolution, and the origins of DNA and DNA-binding proteins2014In: Biochemical Society Transactions, ISSN 0300-5127, E-ISSN 1470-8752, Vol. 42, p. 1159-1167Article in journal (Refereed)
    Abstract [en]

    Nearly 150 different enzymatically modified forms of the four canonical residues in RNA have been identified. For instance, enzymes of the ADAR (adenosine deaminase acting on RNA) family convert adenosine residues into inosine in cellular dsRNAs. Recent findings show that DNA endonuclease V enzymes have undergone an evolutionary transition from cleaving 3' to deoxyinosine in DNA and ssDNA to cleaving 3' to inosine in dsRNA and ssRNA in humans. Recent work on dsRNA-binding domains of ADARs and other proteins also shows that a degree of sequence specificity is achieved by direct readout in the minor groove. However, the level of sequence specificity observed is much less than that of DNA major groove-binding helix-turn-helix proteins. We suggest that the evolution of DNA-binding proteins following the RNA to DNA genome transition represents the major advantage that DNA genomes have over RNA genomes. We propose that a hypothetical RNA modification, a RRAR (ribose reductase acting on genomic dsRNA) produced the first stretches of DNA in RNA genomes. We discuss why this is the most satisfactory explanation for the origin of DNA. The evolution of this RNA modification and later steps to DNA genomes are likely to have been driven by cellular genome co-evolution with viruses and intragenomic parasites. RNA modifications continue to be involved in host-virus conflicts; in vertebrates, edited cellular dsRNAs with inosine-uracil base pairs appear to be recognized as self RNA and to suppress activation of innate immune sensors that detect viral dsRNA.

  • 153. Miele, Rosella
    et al.
    Björklund, Gunnel
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Barra, Donatella
    Simmaco, Maurizio
    Engström, Ylva
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Involvement of Rel factors in the expression of antimicrobial peptide genes in amphibia2001In: European Journal of Biochermistry, Vol. 268, p. 443-449Article in journal (Refereed)
  • 154. Miralles, Francesc
    et al.
    Visa, Neus
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Molecular Characterization of Ct-hrp65.: Identification of Two Novel Isoforms Originated bt Alternative Splicing2001In: Experimental Cell Research, Vol. 264, p. 284-295Article in journal (Refereed)
  • 155.
    Morrison, Jamie I
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Borg, Paula
    Simon, András
    Plasticity and recovery of skeletal muscle satellite cells during limb regeneration2010In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 24, no 3, p. 750-756Article in journal (Refereed)
    Abstract [en]

    Salamander limb regeneration depends on local progenitors whose progeny are recruited to the new limb. We previously identified a Pax7+ cell population in skeletal muscle whose progeny have the potential to contribute to the regenerating limb. However, the plasticity of individual Pax7+ cells, as well as their recovery within the new limb, was unclear. Here, we show that Pax7+ cells remain present after multiple rounds of limb amputation/regeneration. Pax7+ cells are found exclusively within skeletal muscle in the regenerating limb and proliferate where the myofibers are growing. Pax7 is rapidly down-regulated in the blastema, and analyses of clonal derivatives show that Pax7+ cell progeny are not restricted to skeletal muscle during limb regeneration. Our data suggest that the newt regeneration blastema is not entirely a composite of lineage-restricted progenitors. The results demonstrate that except for a transient and subsequently blunted increase, skeletal muscle satellite cells constitute a stable pool of reserve cells for multiple limb regeneration events.

  • 156. Mosesso, Pasquale
    et al.
    Palitti, Fabrizio
    Pepe, Gaetano
    Pinero, Joaquin
    Bellacima, Raffaella
    Ahnström, Gunnar
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Natarajan, Adayapalam T.
    Relationship between chromatin structure, DNA damage and repair following X-irradiation of human lymphocytes2010In: Mutation research. Genetic toxicology and environmental mutagenesis, ISSN 1383-5718, E-ISSN 1879-3592, Vol. 701, no 1, p. 86-91Article in journal (Refereed)
    Abstract [en]

    Earlier studies using the technique of premature chromosome condensation (PCC) have shown that in human lymphocytes, exchange type of aberrations are formed immediately following low doses (<2 Gy) of X-rays, whereas at higher doses these aberrations increase with the duration of recovery. This reflects the relative roles of slow and fast repair in the formation of exchange aberrations. The underlying basis for slow and fast repairing components of the DNA repair may be related to differential localization of the initial damage in the genome, i.e., between relaxed and condensed chromatin. We have tried to gain some insight into this problem by (a) X-irradiating lymphocytes in the presence of dimethyl sulfoxide (DMSO) a potent scavenger of radiation-induced (center dot)OH radicals followed by PCC and (b) probing the damage and repair in two specific chromosomes, 18 and 19, which are relatively poor and rich in transcribing genes by COMET-FISH, a combination of Comet assay and fluorescence in situ hybridization (FISH) techniques. Results obtained show (a) that both fast appearing and slowly formed exchange aberrations seem to take place in relaxed chromatin, since they are affected to a similar extent by DMSO, (b) significant differential DNA breakage of chromosome 18 compared to chromosome 19 in both GO and G1 phases of the cell cycle as detected by Comet assay, indicating that relaxed chromatin containing high densities of transcriptionally active genes shows less fragmentation due to fast repair (chromosome 19) compared to chromosome 18, and (c) that relaxed chromatin is repaired or mis-repaired faster than more compact chromatin.

  • 157. Nashchekin, D
    et al.
    Zhao, J
    Visa, N
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Daneholt, B
    A Novel Ded 1-like RNA Helicase Interacts with the Y-box Protein ctYB-1 in Nuclear mRNA Particles and in Polysomes2006In: Journal of Biological Chemistry, Vol. 281, no 20, p. 14263-14272Article in journal (Refereed)
  • 158. Navon, Ruth
    et al.
    Silberberg, Gilad
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Lundin, Daniel
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Öhman, Marie
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    A Comprehensive Survey of RNA Editing In Psychiatric Disorders Reveals Multiple Novel Editing Sites in Coding Regions2011Conference paper (Refereed)
  • 159.
    Neumann, Nadja
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    The evolution of the nuclear envelope2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The nucleus is one of the defining features of eukaryotes and the question of its origin is intimately linked to the evolution of the eukaryotic cell. It is delimited by a double lipid bilayer called the nuclear envelope, which separates the nuclear interior from the cytoplasm. The inner and outer membranes of the nucleus are continuous with one another creating a single folded envelope, interrupted by nuclear pore complexes (NPCs), which enable transport of proteins and RNA between nucleoplasm and cytoplasm.

    A combination of proteomic and bioinformatic analyses has shown that numerous Nups are conserved between yeast and vertebrates. As this only describes a subset of eukaryotic diversity, comparative genomic analyses were used to establish the extent to which the NPC is conserved across the eukaryotic tree. NPCs have been suggested to share a common origin with vesicle coat proteins of the endomembrane system. An additional goal of this work was therefore to establish the distribution of three complexes involved in vesicle transport between organelles of the secretory pathway, called COPI, COPII and Clathrin.

    Using profile hidden Markov models in combination with BLAST resulted in identification of nucleoporins and coat protein homologs across all five eukaryotic supergroups for which sequence data is available, indicating both were already present in the Last Eukaryotic Common Ancestor (LECA).Nup homologs were shown to be definitively absent from vestigial nucleomorph nuclei, resultant from secondary endosymbioses, suggesting that Nup genes have either been relocated to the host nuclear genome or that the same set of Nups are used for constructing both the NPC of the main nucleus and nucleomorph.´

    We also tested the proposal that transmembrane Nups in vertebrates and yeasts may account for their variant forms of mitosis (‘open’ in vertebrates, ‘closed’ among yeasts). Consistent with this suggestion, the distribution of fungal Pom34 fits a scenario wherein it was integral to the evolution of 'closed’ mitosis in ascomycetes.A unique arrangement for the chromosomes occurs during early meiosis, where the telomeres cluster at the nuclear envelope, forming a distinct ‘bouquet’ arrangement. This forms prior to homolog pairing and recombination in meiosis I. Hypotheses concerning the antiquity of the bouquet were tested by examining the extent of conservation of proteins involved in this stage of meiosis. Distribution appeared patchy, so its presence in LECA could not be unequivocally established and is discussed together with a model aimed at explaining the functional role of the bouquet.

  • 160.
    Neumann, Nadja
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Jeffares, Daniel C.
    Poole, Anthony
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Outsourcing the Nucleus: Nuclear Pore Complex Genes are no Longer Encoded in Nucleomorph Genomes2006In: Evolutionary Bioinformatics, ISSN 1176-9343, E-ISSN 1176-9343, Vol. 2, p. 23-34Article in journal (Refereed)
    Abstract [en]

    The nuclear pore complex (NPC) facilitates transport between nucleus and cytoplasm. The protein constituents of the NPC, termed nucleoporins (Nups), are conserved across a wide diversity of eukaryotes. In apparent exception to this, no nucleoporin genes have been identified in nucleomorph genomes. Nucleomorphs, nuclear remnants of once free-living eukaryotes, took up residence as secondary endosymbionts in cryptomonad and chlorarachniophyte algae. As these genomes are highly reduced, Nup genes may have been lost, or relocated to the host nucleus. However, Nup genes are often poorly conserved between species, so absence may be an artifact of low sequence similarity. We therefore constructed an evolutionary bioinformatic screen to establish whether the apparent absence of Nup genes in nucleomorph genomes is due to genuine absence or the inability of current methods to detect homologues. We searched green plant (Arabidopsis and rice), green alga (Chlamydomonas reinhardtii) and red alga (Cyanidioschyzon merolae) genomes, plus two nucleomorph genomes (Bigelowiella natans and Guillardia theta) with profile hidden Markov models (HMMs) from curated alignments of known vertebrate/yeast Nups. Since the plant, algal and nucleomorph genomes all belong to the kingdom Plantae, and are evolutionarily distant from the outgroup (vertebrate/yeast) training set, we use the plant and algal genomes as internal positive controls for the sensitivity of the searches in nucleomorph genomes. We find numerous Nup homologues in all plant and free-living algal species, but none in either nucleomorph genome. BLAST searches using identified plant and algal Nups also failed to detect nucleomorph homologues. We conclude that nucleomorph Nup genes have either been lost, being replaced by host Nup genes, or, that nucleomorph Nup genes have been transferred to the host nucleus twice independently; once in the evolution of the red algal nucleomorph and once in the green algal nucleomorph.

  • 161.
    Neumann, Nadja
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Lundin, Daniel
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Poole, Anthony M.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Comparative Genomic Evidence for a Complete Nuclear Pore Complex in the Last Eukaryotic Common Ancestor2010In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 5, no 10, p. e13241-Article in journal (Refereed)
    Abstract [en]

    Background: The Nuclear Pore Complex (NPC) facilitates molecular trafficking between nucleus and cytoplasm and is an integral feature of the eukaryote cell. It exhibits eight-fold rotational symmetry and is comprised of approximately 30 nucleoporins (Nups) in different stoichiometries. Nups are broadly conserved between yeast, vertebrates and plants, but few have been identified among other major eukaryotic groups. Methodology/Principal Findings: We screened for Nups across 60 eukaryote genomes and report that 19 Nups (spanning all major protein subcomplexes) are found in all eukaryote supergroups represented in our study (Opisthokonts, Amoebozoa, Viridiplantae, Chromalveolates and Excavates). Based on parsimony, between 23 and 26 of 31 Nups can be placed in LECA. Notably, they include central components of the anchoring system (Ndc1 and Gp210) indicating that the anchoring system did not evolve by convergence, as has previously been suggested. These results significantly extend earlier results and, importantly, unambiguously place a fully-fledged NPC in LECA. We also test the proposal that transmembrane Pom proteins in vertebrates and yeasts may account for their variant forms of mitosis (open mitoses in vertebrates, closed among yeasts). The distribution of homologues of vertebrate Pom121 and yeast Pom152 is not consistent with this suggestion, but the distribution of fungal Pom34 fits a scenario wherein it was integral to the evolution of closed mitosis in ascomycetes. We also report an updated screen for vesicle coating complexes, which share a common evolutionary origin with Nups, and can be traced back to LECA. Surprisingly, we find only three supergroup-level differences (one gain and two losses) between the constituents of COPI, COPII and Clathrin complexes. Conclusions/Significance: Our results indicate that all major protein subcomplexes in the Nuclear Pore Complex are traceable to the Last Eukaryotic Common Ancestor (LECA). In contrast to previous screens, we demonstrate that our conclusions hold regardless of the position of the root of the eukaryote tree.

  • 162.
    Neumann, Nadja
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Poole, Anthony
    Is the bouquet arrangement in meiosis an ancient solution to the hotspot conversion paradox?Manuscript (preprint) (Other academic)
  • 163. Nikravesh, Abbas
    et al.
    Dryselius, Rikard
    Faridani, Omid R
    Goh, Shan
    Sadeghizadeh, Majid
    Behmanesh, Mehrdad
    Ganyu, Anita
    Klok, Erik Jan
    Zain, Rula
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Good, Liam
    Antisense PNA Accumulates in Escheria coli and mediates a Long Post-antibiotic Effect2008In: Molecular Therapy, ISSN 1525-0016, E-ISSN 1525-0024, Vol. 15, no 8, p. 1537-1542Article in journal (Refereed)
    Abstract [en]

    Antisense agents that target growth-essential genes display surprisingly potent bactericidal properties. In particular, peptide nucleic acid (PNA) and phosphorodiamidate morpholino oligomers linked to cationic carrier peptides are effective in time kill assays and as inhibitors of bacterial peritonitis in mice. It is unclear how these relatively large antimicrobials overcome stringent bacterial barriers and mediate killing. Here we determined the transit kinetics of peptide–PNAs and observed an accumulation of cell-associated PNA in Escherichia coli and slow efflux. An inhibitor of drug efflux pumps did not alter peptide–PNA potency, indicating a lack of active efflux from cells. Consistent with cell retention, the post-antibiotic effect (PAE) of the anti-acyl carrier protein (acpP) peptide–PNA was greater than 11 hours. Bacterial cell accumulation and a long PAE are properties of significant interest for antimicrobial development.

  • 164.
    Nord, D.
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Pietrokovski, S.
    Sjöberg, B.-M.
    Ribonucleotide reductase genes as havens for self-splicing elementsManuscript (Other academic)
  • 165.
    Nord, D.
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Sjöberg, B.-M.
    Characterisation of a novel homing endonuclease and screening of intervening sequences in closely related Bacillus thuringiensis nrdIEF genesArticle in journal (Refereed)
  • 166.
    Nord, David
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Homing Endonucleases and Horizontal Gene Transfer in Bacteria and Bacteriophages2007Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Homing endonuclease genes (HEGs) are selfish genetic elements that mediate their own super-Mendelian inheritance. This is mediated by the homing endonuclease cleavage of a HEG- allele followed by recombination-repair with a HEG+ allele.

    The majority of the HEGs are encoded in intervening sequences (IVSs). The insertion of the IVS interrupts the endonuclease recognition site, making the genome with the IVS resistant to further cleavage by homing endonucleases with specificity for that particular sequence, but susceptible for homing endonucleases with a target not affected by the IVS insert. In 39 studied strains of the Bacillus cereus group, 28 IVSs were found in the nrdIEF operon. Phylogenetic studies of these sequences showed a scattered distribution of the IVSs, indicating a frequent horizontal gene transfer and that there might be competition between the different IVSs in the nrdIEF operon in the Bacillaceae family. One novel group I intron was shown to encode a functional homing endonuclease with a GIY-(X)8-YIG motif, expanding the family motif to GIY-(X)8-11-YIG. Interestingly, by studying the known insertion sites for IVSs in the ribonuclotide reductase genes, we show that the majority of the insertions are at conserved motifs, indicating that conservation is important for IVS survival.

    Most freestanding HEGs in bacteriophage T4 cleave both HEG+ and HEG- alleles, possibly providing a competitive advantage for the host organism when two phages infect the same bacterium. Two novel freestanding HEGs replace two putative HEGs in T4 in some T-even-like phages. The characterisation of these HEGs showed that both cleave double stranded DNA. SegH was shown to promote homing of its gene. Hef showed no homing, possibly due to general exclusion of other phages. The mobE putative HEG was shown to be homing proficient and showed strong general DNA degradation when expressed in Escherichia coli.

  • 167.
    Nord, David
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Sjöberg, Britt-Marie
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Unconventional GIY-YIG homing endonuclease encoded in group I introns in closely related strains of the Bacillus cereus group2008In: Nucleic Acids Research, Vol. 36, no 1, p. 300-310Article in journal (Refereed)
  • 168.
    Nord, David
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Torrents, Eduard
    Sjöberg, Britt-Marie
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    A functional homing endonuclease in the Bacillus anthracis nrdE group I intron2007In: Journal of Bacteriology, ISSN 0021-9193, E-ISSN 1098-5530, Vol. 189, no 14, p. 5293-5301Article in journal (Refereed)
    Abstract [en]

    The essential Bacillus anthracis nrdE gene carries a self-splicing group I intron with a putative homing endonuclease belonging to the GIY-YIG family. Here, we show that the nrdE pre-mRNA is spliced and that the homing endonuclease cleaves an intronless nrdE gene 5 nucleotides (nt) upstream of the intron insertion site, producing 2-nt 3' extensions. We also show that the sequence required for efficient cleavage spans at least 4 bp upstream and 31 bp downstream of the cleaved coding strand. The position of the recognition sequence in relation to the cleavage position is as expected for a GIY-YIG homing endonuclease. Interestingly, nrdE genes from several other Bacillaceae were also susceptible to cleavage, with those of Bacillus cereus, Staphylococcus epidermidis (nrdE1), B. anthracis, and Bacillus thuringiensis serovar konkukian being better substrates than those of Bacillus subtilis, Bacillus lichenformis, and S. epidermidis (nrdE2). On the other hand, nrdE genes from Lactococcus lactis, Escherichia coli, Salmonella enterica serovar Typhimurium, and Corynebacterium ammoniagenes were not cleaved. Intervening sequences (IVSs) residing in protein-coding genes are often found in enzymes involved in DNA metabolism, and the ribonucleotide reductase nrdE gene is a frequent target for self-splicing IVSs. A comparison of nrdE genes from seven gram-positive low-G + C bacteria, two bacteriophages, and Nocardia farcinica showed five different insertion sites for self-splicing IVSs within the coding region of the nrdE gene.

  • 169. O'Farrell, Fergal
    et al.
    Seyedoleslami Esfahani, Shiva
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Engström, Ylva
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Kylsten, Per
    Regulation of the Drosophila lin-41 Homologue dappled by let-7 Reveals Conservation of a Regulatory Mechanism Within the LIN-41 Subclade2008In: Developmental Dynamics, ISSN 1058-8388, E-ISSN 1097-0177, Vol. 237, no 1, p. 196-208Article in journal (Refereed)
    Abstract [en]

    Drosophila Dappled (DPLD) is a member of the RBCC/TRIM superfamily, a protein family involved in numerous diverse processes such as developmental timing and asymmetric cell divisions. DPLD belongs to the LIN-41 subclade, several members of which are micro RNA (miRNA) regulated. We re-examined the LIN-41 subclade members and their relation to other RBCC/TRIMs and dpld paralogs, and identified a new Drosophila muscle specific RBCC/TRIM: Another B-Box Affiliate, ABBA. In silico predictions of candidate miRNA regulators of dpld identified let-7 as the strongest candidate. Overexpression of dpld led to abnormal eye development, indicating that strict regulation of dpld mRNA levels is crucial for normal eye development. This phenotype was sensitive to let-7 dosage, suggesting let-7 regulation of dpld in the eye disc. A cell-based assay verified let-7 miRNA down-regulation of dpld expression by means of its 3′-untranslated region. Thus, dpld seems also to be miRNA regulated, suggesting that miRNAs represent an ancient mechanism of LIN-41 regulation.

  • 170.
    Ohlson, Johan
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Novel sites of A-to-I RNA editing in the mammalian brain2007Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The number of protein-coding genes are likely not sufficient to account for the complexity of higher organisms. It is plausible that the proteome is responsible for the complexity of an organism.

    An important mechanism that increases the protein variability is post-transcriptional modifications that alter the pre-mRNA sequence from that encoded in the genome. In this thesis work I have been focusing on a post-transcriptional process where adenosine (A) is deaminated to inosine (I), A-to-I RNA editing. Inosine is read as a guanosine (G) by the translation machinery, editing within coding regions can therefore give rise to more than one protein isoform from a single gene. A-to-I RNA editing is catalyzed by members of the ADAR enzyme family. ADARs have been found in all metazoans tested and two active ADAR proteins, ADAR1 and ADAR2, have been found in mammals. However, recoding by A-to-I editing is a rarely found event in mammals.

    To detect novel substrates for A-to-I editing we developed an experimental approach to pull down ADAR2 substrates using immunoprecipitations. The captured RNAs were identified by microarray analysis. In this thesis two novel substrates for A-to-I editing are presented that were found using our IP-array approach, in combination with bioinformatic techniques.

    The transcript coding for the GABAA receptor subunit α3 (Gabra-3) was found to be selectively edited by both ADAR1 and ADAR2. Editing of Gabra-3 recodes an isoleucine to a methionine and it was found to have a negative effect on the Gabra-3 assembly into the receptor. Moreover, the mouse specific CTN-RNA that codes for the CAT2 Transcribed Nuclear-RNA was shown to be hyper-edited by ADAR2.

    In conclusion, this thesis work has resulted in an experimental method that extracts ADAR substrates. Two novel editing substrates were discovered. Our data adds additional evidence to the fact that RNA editing is of principal significance for a functional brain.

  • 171.
    Ohlson, Johan
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Daniel, Chammiran
    Björk, Petra
    Boije, Henrik
    Hallböök, Finn
    Öhman, Marie
    A-to-I editing regulates GABAA receptor surface expressionManuscript (Other academic)
  • 172.
    Ohlson, Johan
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Ensterö, Mats
    Sjöberg, Britt-Marie
    Öhman, Marie
    A method to find tissue-specific novel sites of selective adenosine deamination2005In: Nucleic Acids Research, ISSN 0305-1048, Vol. 33, no 19, p. e167-Article in journal (Refereed)
  • 173. Ohlson, Johan
    et al.
    Ensterö, Mats
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Sjöberg, Britt-Marie
    Öhman, Marie
    A method to find tissue-specific novel sites of selective adenosine deamination2005In: Nucleic Acids Research, ISSN 0305-1048, Vol. 33, no 19, p. 7-Article in journal (Refereed)
  • 174.
    Ohlson, Johan
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Pedersen, Jakob Skou
    Haussler, David
    Öhman, Marie
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Editing modifies the GABA (A) receptor subunit alpha32007In: RNA, Vol. 13, p. 698-703Article in journal (Refereed)
  • 175.
    Ohlson, Johan
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Skou Pedersen, Jakob
    Haussler, David
    Öhman, Marie
    Editing modifies the GABAA receptor subunit α32007In: RNA, ISSN 1355-8382, Vol. 13, no 5, p. 698-703Article in journal (Refereed)
  • 176.
    Ohlson, Johan
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Wahlstedt, Helene
    Prasanth, Kannanganattu V.
    Spector, David L.
    Öhman, Marie
    ADAR2 edits the CTN-RNA that is retained in the nucleusManuscript (Other academic)
  • 177.
    Ohlson, Johan
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Öhman, Marie
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    A method for finding sites of selective adenosine deamination2007In: Methods in Enzymology, ISSN 0076-6879, E-ISSN 1557-7988, Vol. 424, p. 289-300Article, review/survey (Refereed)
    Abstract [en]

    Single sites of selective adenosine (A) to inosine (1) RNA editing with functional consequences on the proteome are rarely found in mammals. Here we describe a method that can be used to detect novel site-selective A-to-I editing in various tissues as well as species. The method utilizes immunoprecipitation of intrinsic RNA-protein complexes to extract substrates subjected to site-selective in vivo editing. We show that known single sites of A-to-I editing are enriched utilizing an antibody against the ADAR2 protein. We propose that this method is suitable for identification of novel substrates subjected to site-selective A-to-I editing.

  • 178. Oliw, Ernst H.
    et al.
    Jerneren, Fredrik
    Hoffmann, Inga
    Sahlin, Margareta
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Garscha, Ulrike
    Manganese lipoxygenase oxidizes bis-allylic hydroperoxides and octadecenoic acids by different mechanisms2011In: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids, ISSN 1388-1981, E-ISSN 1879-2618, Vol. 1811, no 3, p. 138-147Article in journal (Refereed)
    Abstract [en]

    Manganese lipoxygenase (MnLOX) oxidizes (11R)-hydroperoxylinolenic acid (11R-HpOTrE) to a peroxyl radical. Our aim was to compare the enzymatic oxidation of 11R-HpOTrE and octadecenoic acids with LOO-H and allylic C-H bond dissociation enthalpies of similar to 88 and similar to 87 kcal/mol. Mn(III)LOX oxidized (11Z)-, (12Z)-, and (13Z)-18:1 to hydroperoxides with R configuration, but this occurred at insignificant rates (<1%) compared to 11R-HpOTrE. We next examined whether transitional metals could mimic this oxidation. Ce(4+) and Mn(3+) transformed 11R-HpOTrE to hydroperoxides at C-9 and C-13 via oxidation to a peroxyl radical at C-11, whereas Fe(3+) was a poor catalyst. Our results suggest that MnLOX oxidizes bis-allylic hydroperoxides to peroxyl radicals in analogy with Ce(4+) and Mn(3+). The enzymatic oxidation likely occurs by proton-coupled electron transfer of the electron from the hydroperoxide anion to Mn(III) and H(+) to the catalytic base, Mn(III) OH(-). Hydroperoxides abolish the kinetic lag times of MnLOX and FeLOX by oxidation of their metal centers, but 11R-HpOTrE was isomerized by MnLOX to (13R)-hydroperoxy-(9Z,11E,15Z)-octadecatrienoic acid (13R-HpOTrE) with a kinetic lag time. This lag time could be explained by two competing transformations, dehydration of 11R-HpOTrE to 11-ketolinolenic acid and oxidation of 11R-HpOTrE to peroxyl radical; the reaction rate then increases as 13R-HpOTrE oxidizes MnLOX with subsequent formation of two epoxyalcohols. We conclude that oxidation of octadecenoic acids and bis-allylic hydroperoxides occurs by different mechanisms, which likely reflect the nature of the hydrogen bonds, steric factors, and the redox potential of the Mn(III) center.

  • 179. Penny, D
    et al.
    Hendy, M D
    Poole, A
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Testing fundamental evolutionary hypotheses2003In: The Journal of Theoretical Biology, Vol. 223, p. 377-385Article in journal (Refereed)
  • 180. Penny, D
    et al.
    Poole, A
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Lateral Gene Transfer: Some Theoretical Aspects2003In: NZ BioScience, p. 32-35Article in journal (Other (popular science, discussion, etc.))
  • 181. Penny, David
    et al.
    Hoeppner, Marc P.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Poole, Anthony M.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Jeffares, Daniel C.
    An Overview of the Introns-First Theory2009In: Journal of Molecular Evolution, ISSN 0022-2844, E-ISSN 1432-1432, Vol. 69, p. 527-540Article in journal (Refereed)
    Abstract [en]

    We review the introns-first hypothesis a decade after it was first proposed. It is that exons emerged from

    non-coding regions interspersed between RNA genes in an early RNA world, and is a subcomponent of a more general ‘RNA-continuity’ hypothesis. The latter is that some RNA based systems, especially in RNA processing, are ‘relics’ that can be traced back either to the RNA world that preceded both DNA and encoded protein synthesis or to the later ribonucleoprotein (RNP) world (before DNA took over the main coding role). RNA-continuity is based on independent evidence—in particular, the relative inefficiency of RNA catalysis compared with protein catalysis— and leads to a wide range of predictions, ranging from the origin of the ribosome, the spliceosome, small nucleolar RNAs, RNases P and MRP, and mRNA, and it is consistent with the wide involvement of RNA-processing and regulation of RNA in modern eukaryotes. While there may still

    be cause to withhold judgement on intron origins, there is strong evidence against introns being uncommon in the last eukaryotic common ancestor (LECA), and expanding only within extant eukaryotic groups—the ‘very-late’ intron invasion model. Similarly, it is clear that there are selective forces on numbers and positions of introns; their existence may not always be neutral. There is still a range of viable alternatives, including introns first, early, and ‘latish’ (i.e. well established in LECA), and regardless of which is ultimately correct, it pays to separate out various questions and to focus on testing the predictions of sub-theories.

  • 182.
    Peralvarez-Marin, Alex
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Mateos, Laura
    Zhang, Ce
    Singh, Shalini
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Cedazo-Minguez, Angel
    Visa, Neus
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Morozova-Roche, Ludmilla
    Gräslund, Astrid
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Barth, Andreas
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Influence of Residue 22 on the Folding, Aggregation Profile, and Toxicity of the Alzheimer's Amyloid beta Peptide2009In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 97, no 1, p. 277-285Article in journal (Refereed)
    Abstract [en]

    Several biophysical techniques have been used to determine differences in the aggregation profile (i.e., the secondary structure, aggregation propensity, dynamics, and morphology of amyloid structures) and the effects on cell viability of three variants of the amyloid beta peptide involved in Alzheimer's disease. We focused our study on the Glu(22) residue, comparing the effects of freshly prepared samples and samples aged for at least 20 days. In the aged samples, a high propensity for aggregation and beta-sheet secondary structure appears when residue 22 is capable of establishing polar (Glu(22) in wild-type) or hydrophobic (Val(22) in E22V) interactions. The Arctic variant (E22G) presents a mixture of mostly disordered and a-helix structures (with low beta-sheet contribution). Analysis of transmission electron micrographs and atomic force microscopy images of the peptide variants after aging showed significant quantitative and qualitative differences in the morphology of the formed aggregates. The effect on human neuroblastoma cells of these A beta(12-28) variants does not correlate with the amount of beta-sheet of the aggregates. In samples allowed to age, the native sequence was found to have an insignificant effect on cell viability, whereas the Arctic variant (E22G), the E22V variant, and the slightly-aggregating control (F19G-F20G) had more prominent effects.

  • 183. Percipalle, P
    et al.
    Fomproix, N
    Kylberg, K
    Miralles, F
    Björkroth, B
    Daneholt, B
    Visa, N
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    An actin-ribonucleoprotein interaction is involved in transcription by RNA polymerase II2003In: PNAS, Vol. 100, no 11, p. 6475-6480Article in journal (Refereed)
  • 184. Percipalle, P
    et al.
    Visa, N
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Molecular functions of nuclear actin in transcription2006In: The journal of cell Biology, ISSN 967-971, Vol. 172, no 7Article in journal (Other academic)
  • 185.
    Persson, Bert Ove
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    The iron centre of ribonucleotide reductase protein R2 of Escherichia coli: effects of protein engineering of the iron ligands1997Doctoral thesis, comprehensive summary (Other academic)
  • 186.
    Poole, A
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Getting from an RNA world to modern cells just got a little easier2006In: BioEssays, Vol. 28, no 2, p. 105-108Article in journal (Other academic)
  • 187.
    Poole, A
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Hode, T
    Brandenburg, A
    Holm, N G
    Life Up North: Meeting Report: Nordic Astrobiology 2006: Origins & Distribution of Life in the Universe2006In: Astrobiology, Vol. 6, no 6, p. 815-818Article in journal (Other academic)
  • 188.
    Poole, A
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Logan, D T
    Modern mRNA Proofreading and Repair: Clues that the last Universal Common Ancestor Possessed an RNA Genome?2005In: Mol. Biol. Evol, Vol. 22, no 6, p. 1444-1455Article in journal (Refereed)
  • 189.
    Poole, A M
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Is all that junk really regulatory RNA?2004In: Nature Reviews Genetics, Vol. 5, no 4Article in journal (Other (popular science, discussion, etc.))
  • 190.
    Poole, A
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Phillips, M
    Penny, D
    Prokaryote and eukaryote evolvability2003In: BioSystems, Vol. 69, p. 163-185Article in journal (Refereed)
  • 191.
    Poole, Anthony
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Does endosymbiosis explain the origin of the nucleus?2001In: Nature Cell Biology, Vol. 3, p. E173-Article, book review (Other academic)
  • 192.
    Poole, Anthony
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    My name is LUCA - The Last Universal Common Ancestor2002In: Action BioscienceArticle in journal (Other (popular science, discussion, etc.))
  • 193.
    Poole, Anthony
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Logan, Derek T
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Sjöberg, Britt-Marie
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    The evolution of the ribonucleotide reductases: much ado about oxygen.2002In: J Mol Evol, ISSN 0022-2844, Vol. 55, no 2, p. 180-96Article in journal (Other academic)
    Abstract [en]

    Ribonucleotide reduction is the only known biological means for de novo production of deoxyribonucleotides, the building blocks of DNA. These are produced from ribonucleotides, the building blocks of RNA, and the direction of this reaction has been taken to support the idea that, in evolution, RNA preceded DNA as genetic material. However, an understanding of the evolutionary relationships among the three modern-day classes of ribonucleotide reductase and how the first reductase arose early in evolution is still far off. We propose that the diversification of this class of enzymes is inherently tied to microbial colonization of aerobic and anaerobic niches. The work is of broader interest, as it also sheds light on the process of adaptation to oxygenic environments consequent to the evolution of atmospheric oxygen.

  • 194.
    Poole, Anthony M
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Horizontal gene transfer and the earliest stages of the evolution of life2009In: Research in Microbiology, ISSN 0923-2508, E-ISSN 1769-7123, Vol. 160, no 7, p. 473-480Article in journal (Refereed)
    Abstract [en]

    Horizontal gene transfer (HGT) has been suggested to be the dominant hereditary process at the earliest stages of evolution. I examine this suggestion within the context of the problem of genetic parasites and suggest that extreme rates of transfer may in fact negatively impact evolutionary transitions. In regard to the proposal that HGT is Lamarckian, the apparent conflict between HGT and Darwinian evolution is easily avoided by considering HGT at the appropriate level of selection.

  • 195.
    Poole, Anthony M
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    How the endosymbiont got its cell2009In: New Zeeland Science Review, Vol. 66, no 1, p. 28-33Article, book review (Other academic)
    Abstract [en]

    Despite fundamental advances in cellular, molecular and genome biology, there is still surprisingly little consensus concerning the evolutionary origins of the eukaryote cell. While it is clear that the mitochondrion (responsible for generating much of the energy requirements of the eukaryote cell) has evolved from an endosymbiont cell of bacterial origin, the recent literature has borne witness to a tidal wave of speculative theories regarding the nature of the cell in which this bacterium took up residence. David Penny and I recently argued that much of this confusion can be avoided if models are grounded in known biological processes, and if speculation is tempered by formulating testable hypotheses. The most fanciful hypotheses are an inevitable casualty of a pragmatic approach, but what remains is a productive framework wherein biologically plausible alternatives can be evaluated without the need to invoke ad hoc events or processes, such as biological ‘big bangs’ or hitherto unobserved cell biological phenomena.

  • 196.
    Poole, Anthony M.
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Neumann, Nadja
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Reconciling an archaeal origin of eukaryotes with engulfment: a biologically plausible update of the Eocyte hypothesis2011In: Research in Microbiology, ISSN 0923-2508, E-ISSN 1769-7123, Vol. 162, no 1, p. 71-76Article in journal (Refereed)
    Abstract [en]

    An archaeal origin of eukaryotes is often equated with the engulfment of the bacterial ancestor of mitochondria by an archaeon. Such an event is problematic in that it is not supported by archaeal cell biology. We show that placing phylogenetic results within a stem-and-crown framework eliminates such incompatibilities, and that an archaeal origin for eukaryotes (as suggested from recent phylogenies) can be uncontroversially reconciled with phagocytosis as the mechanism for engulfment of the mitochondrial ancestor. This is significant because it eliminates a perceived problem with eukaryote origins: that an archaeal origin of eukaryotes (as under the Eocyte hypothesis) cannot be reconciled with existing cell biological mechanisms through which bacteria may take up residence inside eukaryote cells.

  • 197.
    Poole, Anthony M.
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Willerslev, Eske
    Can identification of a fourth domain of life be made from sequence data alone, and could it be done on mars?2007In: Astrobiology, ISSN 1531-1074, E-ISSN 1557-8070, Vol. 7, no 5, p. 801-814Article, review/survey (Refereed)
    Abstract [en]

    A central question in astrobiology is whether life exists elsewhere in the universe. If so, is it related to Earth life? Technologies exist that enable identification of DNA- or RNA-based microbial life directly from environmental samples here on Earth. Such technologies could, in principle, be applied to the search for life elsewhere; indeed, efforts are underway to initiate such a search. However, surveying for nucleic acid-based life on other planets, if attempted, must be carried out with caution, owing to the risk of contamination by Earth-based life. Here we argue that the null hypothesis must be that any DNA discovered and sequenced from samples taken elsewhere in the universe are Earth-based contaminants. Experience from studies of low-biomass ancient DNA demonstrates that some results, by their very nature, will not enable complete rejection of the null hypothesis. In terms of eliminating contamination as an explanation of the data, there may be value in identification of sequences that lie outside the known diversity of the three domains of life. We therefore have examined whether a fourth domain could be readily identified from environmental DNA sequence data alone. We concluded that, even on Earth, this would be far from trivial, and we illustrate this point by way of examples drawn from the literature. Overall, our conclusions do not bode well for planned PCR-based surveys for life on Mars, and we argue that other independent biosignatures will be essential in corroborating any claims for the presence of life based on nucleic acid sequences.

  • 198.
    Poole, Anthony
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Penny, David
    Engulfed by speculation2007In: Nature, Vol. 447, no 913Article in journal (Other academic)
  • 199.
    Poole, Anthony
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Penny, David
    Evaluating hypotheses for the origin of eukaryotes2007In: BioEssays, Vol. 29, p. 74-84Article in journal (Refereed)
  • 200.
    Poole, Anthony
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Penny, David
    Response to Dagan and Martin2007In: BioEssays, Vol. 29, p. 611-614Article in journal (Other academic)
1234567 151 - 200 of 304
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