@article{SpringTrendelenbrugScheeretal.1974,
  author    = {Spring, Herbert and Trendelenbrug, Michael F. and Scheer, Ulrich and Franke, Werner W. and Herth, Werner},
  title     = {Structural and biochemical studies of the primary nucleus of two green algal species, Acetabularia mediterranea and Acetabularia major},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-40600},
  year      = {1974},
  abstract  = {Primary (giant) nuclei of the green algae Acetabularia mediterranea and A. major were studied by light and electron microscopy using in situ fixed material as well as manually isolated nuclear components. In addition, cytochemical reactions of nuclear structures and biochemical determinations of nuclear and cytoplasmic RNA and of genome DNA content were performed. The data obtained and the structures observed are interpreted as demonstralions of transcriptional activities of different gene classes. The most prominent class is the nucleolar cistrons of precursors of ribosomal RNA which occur highly repeated in clusters in the form of regularly alternating intercepts on deoxyribonucleoprotein axes of transcribed rDNA, the fibril-covered matrix units, and the fibril-free "spacer" segments. A description and a classification of the various structural complexes which seem to represent transcriptional activities is given. Quantitative evaluations of these arrangements are presented. The morphology and the dimensions of such structures are compared with the RNA molecular weight determinations and with the corresponding data reported from various animal cell systems. It is suggested that the formation of the giant nucleus is correlated with, and probably due to, an enormous amplification of transcriptionally active rDNA and packing of the extrachromosomal copies into the large nucleolar aggregate bodies.},
  subject      = {Cytologie},
  language  = {en}
}
@article{FrankeScheerTrendelenburgetal.1976,
  author    = {Franke, Werner W. and Scheer, Ulrich and Trendelenburg, Michael F. and Spring, Herbert and Zentgraf, Hanswalter},
  title     = {Absence of nucleosomes in transcriptionally active chromatin},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-40646},
  year      = {1976},
  abstract  = {The ultrastructure of twO kinds of transcription ally active chromatin, the lampbrush chromosome loops and the nucleoli from amphibian oocytes and primary nuclei of the green alga Acetabularia, has been examined after manual isolation and dispersion in low salt media of slightly alkaline pH using various electron microscopic staining techniques (positive staining, metal shadowing, negative staining, preparation on positively charged films, etc.) and compared with the appearance of chromatin from various somatic cells (hen erythrocytes, rat hepatocytes, ClIltured murine sarcoma cells) prepared in parallel. While typical nucleosomes were revealed with all the techniques for chromatin from the latter three cell system, no nucleosomes were identified in either the lampbrush chromosome structures or the nucleolar chromatin. Nucleosomal arrays were absent not only in maximally fibril-covered matrix units but also in fibril-free regions between transcriptional complexes, including the apparent spacer intercepts between different transcriptional units. Moreover, comparisons of the length of the repeating units of rDNA in the transcribed state with those determined in the isolated rDNA and with the lengths of the first stable product of rDNA transcription, the pre-rRNA, demonstrated that the transcribed rDNA was not significantly shortened and/or condensed but rather extended in the transcriptional units. Distinct granules of about nucleosomal size which were sometimes found in apparent spacer regions as well as within matrix units of reduced fibril density were shown not to represent nucleosomes since their number per spacer unit was not inversely correlated with the length of the specific unit and also on the basis of their resistance to treatment with the detergent Sarkosyl NL-30. It is possible to structurally distinguish between transcriptionally active chromatin in which the DNA is extended in a non-nucleosomal form of chromatin and condensed, inactive chromatin within the typical nucleosomal package. The characteristic extended structure of transcriptionally active chromatin is found not only in the transcribed genes but also in non-transcribed regions within or between ("spacer") transcriptional units as well as in transcriptional units that are untranscribed amidst transcribed ones and/or have been inactivated for relatively short time. It is hypothesized that activation of transcription involves a transition from a nucleosomal to an extended chromatin organisation and that this structural transition is not specific for single "activated" genes but may involve larger chromatin regions, including adjacent untranscribed intercepts.},
  subject      = {Cytologie},
  language  = {en}
}
@phdthesis{Spohn1999,
  author    = {Spohn, Gunther},
  title     = {The transcriptional control of virulence gene expression in Helicobacter pylori},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-2334},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {1999},
  abstract  = {The Gram-negative, spiral-shaped, microaerophilic bacterium Helicobacter pylori is the causative agent of various disorders of the upper gastrointestinal tract, such as chronic superficial gastritis, chronic active gastritis, peptic ulceration and adenocarcinoma. Although many of the bacterial factors associated with disease development have been analysed in some detail in the recent years, very few studies have focused so far on the mechanisms that regulate expression of these factors at the molecular level. In an attempt to obtain an overview of the basic mechanisms of virulence gene expression in H. pylori, three important virulence factors of this pathogen, representative of different pathogenic mechanisms and different phases of the infectious process, are investigated in detail in the present thesis regarding their transcriptional regulation. As an essential factor for the early phase of infection, including the colonisation of the gastric mucosa, the flagella are analysed; the chaperones including the putative adhesion factors GroEL and DnaK are investigated as representatives of the phase of adherence to the gastric epithelium and persistence in the mucus layer; and finally the cytotoxin associated antigen CagA is analysed as representative of the cag pathogenicity island, which is supposed to account for the phenomena of chronic inflammation and tissue damage observed in the later phases of infection. RNA analyses and in vitro transcription demonstrate that a single promoter regulates expression of cagA, while two promoters are responsible for expression of the upstream divergently transcribed cagB gene. All three promoters are shown to be recognised by RNA polymerase containing the vegetative sigma factor sigma 80. Promoter deletion analyses establish that full activation of the cagA promoter requires sequences up to -70 and binding of the C-terminal portion of the alpha subunit of RNA polymerase to an UP-like element located between -40 and -60, while full activation of the major cagB promoter requires sequences upstream of -96 which overlap with the cagA promoter. These data suggest that the promoters of the pathogenicity island represent a class of minimum promoters, that ensure a basic level of transcription, while full activation requires regulatory elements or structural DNA binding proteins that provide a suitable DNA context. Regarding flagellar biosynthesis, a master transcriptional factor is identified that regulates expression of a series of flagellar basal body and hook genes in concert with the alternative sigma factor sigma 54. Evidence is provided that this regulator, designated FlgR (for flagellar regulatory protein), is necessary for motility and transcription of five promoters for seven basal body and hook genes. In addition, FlgR is shown to act as a repressor of transcription of the sigma 28-regulated promoter of the flaA gene, while changes in DNA topology are shown to affect transcription of the sigma 54-regulated flaB promoter. These data indicate that the regulatory network that governs flagellar gene expression in H. pylori shows similarities to the systems of both Salmonella spp. and Caulobacter crescentus. In contrast to the flagellar genes which are regulated by three different sigma factors, the three operons encoding the major chaperones of H. pylori are shown to be transcribed by RNA polymerase containing the vegetative sigma factor sigma 80. Expression of these operons is shown to be regulated negatively by the transcriptional repressor HspR, a homologue of a repressor protein of Streptomyces spp., known to be involved in negative regulation of heat shock genes. In vitro studies with purified recombinant HspR establish that the protein represses transcription by binding to large DNA regions centered around the transcription initiation site in the case of one promoter, and around -85 and -120 in the case of the the other two promoters. In contrast to the situation in Streptomyces, where transcription of HspR-regulated genes is induced in response to heat shock, transcription of the HspR-dependent genes in H. pylori is not inducible with thermal stimuli. Transcription of two of the three chaperone encoding operons is induced by osmotic shock, while transcription of the third operon, although HspR-dependent, is not affected by salt treatment. Taken together, the analyses carried out indicate that H. pylori has reduced its repertoire of specific regulatory proteins to a basic level that may ensure coordinate regulation of those factors that are necessary during the initial phase of infection including the passage through the gastric lumen and the colonisation of the gastric mucosa. The importance of DNA topology and/or context for transcription of many virulence gene promoters may on the other hand indicate, that a sophisticated global regulatory network is present in H. pylori, which influences transcription of specific subsets of virulence genes in response to changes in the microenvironment.},
  subject      = {Helicobacter-pylori-Infektion},
  language  = {en}
}
@phdthesis{Mauder2006,
  author    = {Mauder, Norman},
  title     = {Vergleichende Untersuchung der Internaline und PrfA-abh{\"a}ngigen Transkription in Listeria monocytogenes, L. ivanovii und L. seeligeri},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-21659},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2006},
  abstract  = {Die Gattung Listeria umfasst sechs bekannte Arten ubiquit{\"a}r vorkommender Gram-positiver, nicht sporulierender St{\"a}bchenbakterien. Von diesen Spezies sind Listeria monocytogenes und L. ivanovii in der Lage bei Mensch und Tier das Krankheitsbild der Listeriose zu verursachen (Rocourt \& Seeliger, 1985; V{\´a}zquez-Boland et al., 2001b; Weis \& Seeliger, 1975), wobei L. ivanovii vorwiegend bei Tieren als Krankheitserreger vorkommt (Cummins et al., 1994; Hof \& Hefner, 1988). L. monocytogenes gilt als wichtiges Modell f{\"u}r ein intrazellul{\"a}res Pathogen, das mit Hilfe seiner Internaline auch in nicht-professionelle Phagozyten invadieren (Gaillard et al., 1991; Lingnau et al., 1995) und sich dank einer Reihe weiterer Virulenzfaktoren im Zytoplasma vermehren, fortbewegen und Nachbarzellen infizieren kann (Tilney \& Portnoy, 1989). Die beiden pathogenen Arten und das apathogene L. seeligeri besitzen eine als LIPI-1 bezeichnete Pathogenit{\"a}tsinsel (Gouin et al., 1994; Kreft et al., 2002). Internalingene sind bei L. monocytogenes teilweise geclustert und bei L. ivanovii zu einem großen Teil in einer LIPI-2 genannten Pathogenit{\"a}tsinsel organisiert (Dom{\´i}nguez-Bernal et al., 2006; Dramsi et al., 1997; Gaillard et al., 1991; Raffelsbauer et al., 1998). Die Expression vieler dieser Virulenzgene wird durch das zentrale Regulatorprotein PrfA gesteuert, dessen Gen prfA selbst Teil der LIPI-1 ist (Dom{\´i}nguez-Bernal et al., 2006; Leimeister-W{\"a}chter et al., 1990; Lingnau et al., 1995; Mengaud et al., 1991a). Im Rahmen dieser Arbeit sollten die Internaline InlC, InlE, InlG und InlH von L. monocytogenes n{\"a}her untersucht werden. Dazu wurden rekombinante His6-markierte Internaline aufgereinigt und polyklonale Antiseren gegen die Internaline A, B, E, G und H hergestellt. Dar{\"u}ber hinaus gelang die Herstellung zweier monoklonaler Antik{\"o}rper gegen InlG. Obwohl die Antik{\"o}rper gegen InlG und InlE ihre rekombinanten Antigene gut dekorieren, konnten mit ihnen keine Proteine in Zellwand- oder {\"U}berstandspr{\"a}paraten von L. monocytogenes EGD und EGDe detektiert werden. Das Antiserum gegen InlH kreuzreagierte mit InlA und auch schwach mit anderen Internalinen. In Zellwandpr{\"a}paraten von L. monocytogenes dekorierte es ein ~50 kDa schweres Protein, welches mit InlH identisch sein k{\"o}nnte. Es fehlt in inlG/H/E Deletionsmutanten und wird in einer inlA/B Deletionsmutante st{\"a}rker exprimiert. Im Kultur{\"u}berstand ist es etwas schwerer, wie man es von einem Protein mit LPXTG Motiv erwartet, das nicht von Sortase (Bierne et al., 2002; Garandeau et al., 2002) prozessiert wurde. In L. monocytogenes EGDe wird dieses ~50 kDa Protein um ein bis zwei dekadische Gr{\"o}ßenordungen st{\"a}rker exprimiert als in L. monocytogenes EGD. Die Expression des Proteins war bei 30 und 37 °C gleich stark und wurde nicht durch PrfA reguliert. In Zellwandpr{\"a}paraten von L. ivanovii ATCC 19119 dekorierten die Seren gegen InlA und InlH ein Protein das in seiner Gr{\"o}ße dem InlA von L. monocytogenes entspricht. Mit Hexosaminidase Assays zur Untersuchung von Zelladh{\"a}renz (nach Landegren, 1984) an rekombinante His6-markierte Internaline konnte keine Interaktion der Internaline InlE, InlG oder InlH mit Oberfl{\"a}chenfaktoren von Caco-2, HeLa oder HepG2 Zellen nachgewiesen werden, w{\"a}hrend Positivkontrollen mit InlA und InlB weitestgehend erwartungsgem{\"a}ß ausfielen. InlC besitzt jedoch offenbar einen bisher noch nicht genauer identifizierten Rezeptor auf der Zelloberfl{\"a}che. An InlC und EGF adh{\"a}rierten Caco-2 Zellen stark wachstumsphasenabh{\"a}ngig und etwa tausendfach schw{\"a}cher als an InlA. Die beste Bindung erfolgte bei semikonfluent gewachsenen Zellen, die am Vortag ausges{\"a}t wurden. Unter diesen Bedingungen war auch die von Bergmann et al. beobachtete unterst{\"u}tzende Wirkung von InlC auf die InlA-abh{\"a}ngige Invasion am gr{\"o}ßten (Bergmann et al., 2002). In dieser Arbeit wurden außerdem die Promotoren von Internalingenen aus L. ivanovii, sowie weitere Virulenzgene (plcA, hly, actA) der Spezies L. monocytogenes, L. ivanovii und L. seeligeri mit Hilfe eines zellfreien in vitro Transkriptionssystems (Lalic-M{\"u}lthaler et al., 2001) untersucht, um deren PrfA-Abh{\"a}ngigkeit und Aktivit{\"a}t unabh{\"a}ngig von physiologischen Faktoren analysieren zu k{\"o}nnen, da die PrfA-Aktivit{\"a}t in vivo pleiotrop reguliert wird (Dickneite et al., 1998; Ermolaeva et al., 2004; Milenbachs et al., 1997; Milenbachs Lukowiak et al., 2004; Renzoni et al., 1997; Ripio et al., 1996). Daf{\"u}r wurde in dieser Arbeit RNA-Polymerase aus L. monocytogenes \&\#916;prfA \&\#916;sigB (Stritzker et al., 2005) isoliert. Gleichzeitig wurde die Aktivit{\"a}t von rekombinanten His6-markierten PrfA Proteinen untersucht. Dazu wurden die PrfA Proteine von L. monocytogenes (m-PrfA und hyperaktives m-PrfA* (Ripio et al., 1997b)), L. ivanovii (i-PrfA) und L. seeligeri (s-PrfA), so wie ein Hybridprotein (sm-PrfA) aufgereinigt. Das Hybridprotein sm-PrfA entspricht s-PrfA bis auf die letzten 38 Aminos{\"a}urereste, die durch jene von m-PrfA ersetzt wurden. ...},
  subject      = {Listeria},
  language  = {de}
}
@phdthesis{Osterloh2007,
  author    = {Osterloh, Lisa},
  title     = {Identifizierung und Charakterisierung LIN-9 regulierter Gene im humanen System - Die Rolle von LIN-9 in der Regulation des Zellzyklus},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-24360},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2007},
  abstract  = {Das humane LIN-9 wurde zuerst als pRB-interagierendes Protein beschrieben und spielt eine Rolle als Tumorsuppressor im Kontext des pRB-Signalweges. {\"U}ber die molekulare Funktion von LIN-9 ist jedoch wenig bekannt. Die Homologe von LIN-9 in D. melanogaster und in C. elegans, sind an der transkriptionellen Regulation verschiedener Genen beteiligt. Dies und die Tatsache, dass LIN-9 mit pRB in der Aktivierung differenzierungspezifischer Gene kooperiert, ließ vermuten, dass humanes LIN-9 einen bedeutenden Einfluss auf die transkriptionelle Regulation von Genen haben k{\"o}nnte. Prim{\"a}res Ziel dieser Arbeit war daher die Identifizierung LIN-9 regulierter Gene. Dazu sollte mit Hilfe von cDNA-Microarray Analysen, das Genexpressionsprofil LIN-9 depletierter prim{\"a}rer humaner Fibroblasten (BJ ET Zellen) im Vergleich zu Kontrollzellen untersucht werden. Hierf{\"u}r wurde zun{\"a}chst ein RNAi-basierendes System etabliert, um die posttranskriptionelle Expression von LIN-9 in BJ-ET Zellen effizient zu reprimieren. Auf dem Ergebnis der cDNA-Microarray Analysen aufbauende Untersuchungen sollten Aufschluss {\"u}ber die molekularbiologische Funktion von LIN-9 geben. In dieser Arbeit konnte erstmals gezeigt werden, dass der Verlust von LIN-9 zu einer verminderten Expression einer Gruppe G2/M-spezifischer Gene f{\"u}hrt, deren Produkte f{\"u}r den Eintritt in die Mitose ben{\"o}tigt werden. Bekannt war, dass ein Teil dieser Gene durch den Transkriptionsfaktor B-MYB koreguliert wird. Zudem konnten Untersuchungen in unserem Labor eine Interaktion von LIN-9 und B-MYB auf Proteinebene, sowie die Bindung beider Proteine an die Promotoren der LIN-9 regulierten G2/M-Gene nachweisen. Dies l{\"a}sst vermuten, dass LIN-9 und B-MYB gemeinsam die Expression der G2/M-Gene kontrollieren. Die verminderte Expression von G2/M-Genen in LIN-9 bzw. B-MYB depletierten Zellen geht mit einer Reihe ph{\"a}notypischer Ver{\"a}nderungen einher, wie einer deutlich verlangsamten Proliferation und einer Akkumulation der Zellen in der G2/M-Phase. Mit Hilfe eines Durchflusszytometers erstellte Zellzykluskinetiken ergaben, dass die Progression LIN-9 bzw. B-MYB depletierter Fibroblasten von der S-Phase durch die G2/M-Phase und in die n{\"a}chste G1-Phase deutlich verz{\"o}gert ist. Es konnte weder ein Arrest dieser Zellen in der Mitose noch eine ver{\"a}nderte L{\"a}nge der S-Phase nach LIN-9 oder B-MYB Depletion festgestellt werden. Daher ist die verlangsamte Zellzyklusprogression nach LIN-9 bzw. B-MYB Verlust h{\"o}chstwahrscheinlich auf einen Defekt in der sp{\"a}ten G2-Phase zur{\"u}ckzuf{\"u}hren, welcher in einem verz{\"o}gerten Eintritt in die Mitose resultiert. In D. melanogaster und in C. elegans sind die Homologe von LIN-9 und B-MYB zusammen, als Bestandteile hoch konservierter RB/E2F-Komplexe, an der Regulation von Genen entscheidend beteiligt. Daher liegt es nahe, dass im humanen System LIN-9 und B MYB ebenfalls Bestandteile eines {\"a}hnlichen Komplexes sind und dadurch die Aktivierung der LIN 9 abh{\"a}ngigen G2/M-Gene vermitteln. Die Tatsache, dass LIN-9 sowohl als Tumorsuppressor, als auch als positiver Regulator des Zellzyklus fungiert, l{\"a}sst vermuten, dass LIN-9 zu einer stetig gr{\"o}ßer werdenden Gruppe von Proteinen geh{\"o}rt, welche in Abh{\"a}ngigkeit vom zellul{\"a}ren und genetischen Kontext sowohl tumorsuppressive als auch onkogene Funktionen besitzen.},
  subject      = {Zellzyklus},
  language  = {de}
}
@phdthesis{Schmit2008,
  author    = {Schmit, Fabienne},
  title     = {LINC, a novel protein complex involved in the regulation of G2/M genes},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-29336},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2008},
  abstract  = {Regulated progression through the cell cycle is essential for ordered cell proliferation. One of the best characterized tumor suppressors is the retinoblastoma protein pRB, which together with the E2F transcription factors regulates cell cycle progression. In the model organisms Drosophila melanogaster and Caenorhabditis elegans, RB/E2F containing multiprotein complexes have been described as transcriptional regulators of gene expression. This work first describes a homologous complex in human cells named LINC (for LIN complex). It consists of a stable core complex containing LIN-9, LIN-37, LIN-52, LIN-54 and RbAp48. This core complex interacts cell cycle-dependently with different pocket proteins and transcription factors. In quiescent cells, LINC associates with p130 and E2F4. In S-phase cells these interactions are lost and LINC binds to B-MYB and p107. The transient knock-down of LIN-54 in primary fibroblasts, as the depletion of LIN-9, leads to cell cycle defects. The cells are delayed before the entry into mitosis. This effect is due to the fact that the knock-down of LINC components leads to the downregulation of cell cycle genes responsible for the entry into and exit from mitosis as well as for checkpoints during mitosis. These LINC target genes are known E2F G2/M target genes, which are expressed later than the classical G1/S E2F target genes. The transcriptional regulation by LINC is a direct effect as LINC binds to the promoters of its target genes throughout the cell cycle. LINC contains three DNA-binding proteins. E2F4 and B-MYB, which cell cycle-dependently bind to LINC, are known DNA-binding transcription factors. Additionally, it is show here that the LINC core complex member LIN-54 also directly binds to the promoter of a LINC target gene. Although the exact molecular mechanism of LINC function needs to be analyzed further, data in this work provide a model for the delayed activation of G2/M target genes. B-MYB, a G1/S E2F target gene, binds to LINC upon its expression in S-phase. Then only LINC is a transcriptional activator that induces the expression of the G2/M genes. This provides an explanation for the delayed expression of these E2F G2/M target genes.},
  subject      = {Zellzyklus},
  language  = {en}
}
@phdthesis{Markert2009,
  author    = {Markert, Andreas},
  title     = {LARP7 - ein La {\"a}hnliches Protein reguliert die Elongation der PolII Transkription durch das 7SK RNP},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-41773},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2009},
  abstract  = {Genexpression in Eukaryoten beschreibt einen mehrstufigen Prozess, welcher auf Ebene der Transkription durch den positiven Transkriptionselongationsfaktor P-TEFb entscheidend reguliert wird. PTEFb bildet einen heterodimeren Komplex aus der Cyclin abh{\"a}ngigen Kinase 9 und deren Kofaktor Cyclin T1/2. Dieser Komplex aktiviert die Elongation der Transkription durch Phosphorylierung der negativen Elongationsfaktoren DSIF und NELF. Dar{\"u}ber hinaus phosphoryliert PTEFb Serin2 Reste in der C-terminalen Dom{\"a}ne von RNA PolII und stimuliert so die kotranskriptionelle Prozessierung der synthetisierten pr{\"a}-mRNA. In Anpassung an unterschiedliche Wachstumsbedingungen wird die Aktivit{\"a}t dieses Faktors durch reversible Interaktion mit 7SK RNA und HEXIM Proteinen innerhalb eines katalytisch inaktiven Ribonukleoproteinpartikels (7SK RNP) streng kontrolliert. Dieses sensible Gleichgewicht zwischen P-TEFb auf der einen und dem 7SK RNP auf der anderen Seite bildet die Grundlage der Regulation der Transkriptionselongation. Trotz der hohen Abundanz von 7SK RNA in der Zelle, assoziiert in vivo jedoch nur ein relativ kleiner Teil hiervon mit P-TEFb, sodass die effektiv zur Verf{\"u}gung stehende RNA-Menge f{\"u}r die Bildung des 7SK RNP vermutlich limitierend wirkt. Ziel der vorliegenden Arbeit war es daher neue 7SK RNA interagierende Faktoren zu identifizieren, welche die Interaktion von PTEFb mit dem 7SK RNP steuern und so die PolII abh{\"a}ngige Transkription regulieren. Anhand verschiedener chromatographischer Reinigungen konnte zun{\"a}chst ein bislang uncharakterisiertes La {\"a}hnliches Protein (LARP7) mit einer spezifischen Affinit{\"a}t f{\"u}r Pyrimidinreiche RNAs isoliert werden. LARP7 bindet, wie durch immunbiochemische Analysen und RNA- Bindungsstudien gezeigt werden konnte, quantitativ an das hoch konservierte uridylreiche 3´- Ende von 7SK RNA. Diese Assoziation erfordert dessen La- und RRMDom{\"a}nen und erh{\"o}ht wesentlich die Stabilit{\"a}t der RNA. Dar{\"u}ber hinaus kofraktioniert LARP7 mit weiteren Faktoren des 7SK RNP, bindet direkt an HEXIM1 und P-TEFb und stellt somit ebenfalls eine integrale Komponente des 7SK RNP dar. Die gewonnenen Daten weisen außerdem erstmals darauf hin, dass P-TEFb durch einen vorgeformten trimeren Komplexes, bestehend aus HEXIM1, 7SK RNA und LARP7 inhibiert wird. Reportergenanalysen in TZMbl-Zellen, welche Luziferase unter der Kontrolle des streng P-TEFb abh{\"a}ngigen HIV-1-LTRPromotors exprimieren zeigten, dass diese Inhibition im Wesentlichen durch LARP7 vermittelt wird. So ließ sich nach Reduktion der LARP7 Expression mittels RNAi eine signifikante Steigerung der Transkription vom HIV-1-LTR-Promotor beobachten. Eine {\"a}hnliche Stimulation der Transkription von PolII konnte in LARP7 defizienten HeLa-Zellen durch quantitative Real-Time-PCR auch f{\"u}r eine Reihe zellul{\"a}rer Gene nachgewiesen werden. Die Beobachtung, dass LARP7 die generelle PolII Transkription reprimiert, korreliert zudem mit einer bereits beschriebenen Tumorsupressorfunktion des LARP7 homologen mxc Proteins aus D. melanogaster. Somit beeinflusst LARP7 das zellul{\"a}re Gleichgewicht zwischen freiem und 7SK RNP-gebundenem P-TEFb und fungiert somit als negativer Regulator der PolII Transkription in vivo.},
  subject      = {LARP7},
  language  = {de}
}
@phdthesis{Fischer2010,
  author    = {Fischer, Thomas Horst},
  title     = {Die transkriptionelle Regulation der microRNA-21 im Herzen},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-50702},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2010},
  abstract  = {MicroRNAs sind kleine, nicht kodierende RNA-Molek{\"u}le, die posttranskriptionell die Genexpression regulieren. Sie binden hierf{\"u}r spezifisch an 3'-UTRs von messenger-RNAs und f{\"u}hren entweder direkt zu deren Abbau oder inhibieren deren Translation. {\"U}ber die Mechanismen, die die Expression von microRNAs regulieren, ist jedoch noch wenig bekannt. Die Tatsache, dass sie als lange Vorl{\"a}ufermolek{\"u}le (pri-microRNAs) durch die RNA-Polymerase-II transkribiert werden, legt die Existenz eines Promotorbereiches nahe, der dem proteinkodierender Gene {\"a}hnelt. Mit Hilfe von microRNA-Arrays konnten wir im linksventrikul{\"a}ren Myokard mehrere bei Herzinsuffizienz deutlich ver{\"a}ndert exprimierte microRNAs identifizieren. Die microRNA-21 ist dabei bereits im Fr{\"u}hstadium der Herzinsuffizienz verst{\"a}rkt exprimiert (Northern Blot). Auch in prim{\"a}ren, kardialen Zellen (Fibroblasten, Kardiomyozyten) wird die microRNA-21 nach Induktion einer Hypertrophie verst{\"a}rkt exprimiert. Weiterf{\"u}hrendes Ziel dieser Arbeit war es nun, diejenigen Mechanismen aufzukl{\"a}ren, die der starken Induktion der microRNA-21 im erkrankten Myokard zu Grunde liegen. Durch bioinformatische Analyse des zugeh{\"o}rigen Promotorbereiches (Trans-Spezies-Konservierung) und Klonierung danach ausgerichteter Fragmente in Luciferase-basierte Reporter-Plasmide konnte ein 118 Basen langer Bereich identifiziert werden, der maßgeblich die Expression der microRNA-21 im Herzen bedingt. Durch Deaktivierung einzelner cis-Elemente konnte die kardiale Expression auf zwei essentielle Transkriptionsfaktorbindungsstellen zur{\"u}ckgef{\"u}hrt werden. Es handelt sich dabei um Erkennungssequenzen f{\"u}r die im Herz bedeutsamen Transkriptionsfaktoren CREB und SRF. Sie liegen in enger r{\"a}umlicher Nachbarschaft ungef{\"a}hr 1150 bp vor der Transkriptionsstartstelle. Die Suppression der Expression dieser beiden Transkriptionsfaktoren mittels geeigneter siRNAs f{\"u}hrte jeweils zu einer signifikanten Aktivit{\"a}tsminderung des microRNA-21-Promotors und konnte somit die vorangehenden Ergebnisse validieren. Durch Generierung einer transgenen Tierlinie, die lacZ unter der Kontrolle des microRNA-21-Promotors exprimiert, werden in naher Zukunft n{\"a}here Aufschl{\"u}sse {\"u}ber die gewebsspezifische Verteilung der microRNA-21-Expresssion in vivo m{\"o}glich sein. Zusammenfassend beschreiben wir hier erstmals den Mechanismus der transkriptionellen Regulation der microRNA-21 im Herzen. Dieser Mechanismus bedingt wahrscheinlich die starke Induktion dieser microRNA bei kardialer Hypertrophie und Herzinsuffizienz.},
  subject      = {Small RNA},
  language  = {de}
}
@phdthesis{Effenberger2012,
  author    = {Effenberger, Madlen},
  title     = {Funktionelle Charakterisierung von YB-1 im Zytoplasma des Multiplen Myeloms},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-76816},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2012},
  abstract  = {Das Y-Box-bindende Protein 1 (YB-1) ist ein Vertreter der hochkonservierten Familie eukaryotischer K{\"a}lteschockproteine und ein DNA/RNA-bindendes Protein. In Abh{\"a}ngigkeit von seiner Lokalisation {\"u}bernimmt es Aufgaben bei der DNA-Transkription oder mRNA-Translation. YB-1 ist ein potentielles Onkogen beim Multiplen Myelom (MM), dass in prim{\"a}ren MM-Zellen exprimiert ist. F{\"u}r die funktionellen Untersuchungen von YB-1 in der vorliegenden Arbeit wurden humane Myelomzelllinien (HMZL) verwendet, die als in vitro Modell dieser malignen B Zell-Erkrankung dienen. Aufgrund der potentiellen Expression von YB-1 im Zellkern und/oder Zytoplasma von HMZL, wurde zun{\"a}chst die Lokalisation des Proteins bestimmt. Es konnte gezeigt werden, dass YB 1 in den HMZL ausschließlich im Zytoplasma lokalisiert ist. Eine Translokation von YB-1 in den Nukleus kann durch die Serin-Phosphorylierung (Aminos{\"a}ure 102) in der K{\"a}lteschockdom{\"a}ne induziert werden. Die analysierten Myelomzelllinien zeigen jedoch kein nukle{\"a}res YB 1 und keine S102-Phosphorylierung. Diese Ergebnisse st{\"u}tzen die These, dass die Regulation der mRNA-Translation im Zytoplasma die vorherrschende Funktion von YB-1 beim MM ist. YB-1 k{\"o}nnte {\"u}ber diesen Mechanismus seine anti-apoptotische Wirkung vermitteln und die MM-Zellen vor genotoxischem Stress sch{\"u}tzen. Um YB-1-regulierte mRNAs zu identifizieren wurden YB 1-Immunpr{\"a}zipitationen mit zwei HMZL, einer Maus-Plasmozytomzelllinie und einem prim{\"a}ren Maus-Plasmazelltumor durchgef{\"u}hrt. Zu den YB-1-gebundenen mRNAs geh{\"o}ren Translationsfaktoren und ribosomale Proteine, die eine starke Beteiligung von YB-1 beim RNA-Metabolismus best{\"a}tigen. In der vorliegenden Arbeit wurden spezifisch zwei mRNA-Kandidaten untersucht, die f{\"u}r den malignen Ph{\"a}notyp von MM-Zellen wichtig sein k{\"o}nnen: das translationell kontrollierte Tumorprotein TCTP und MYC. Sowohl TCTP als auch MYC wurden bereits in Zusammenhang mit der Proliferation und Apoptose-Resistenz von malignen Zellen beschrieben. Die immunhistochemische Untersuchung der Knochenmarkbiopsien von MM-Patienten ergab eine gute Ko-Expression von YB-1 und TCTP in intramedull{\"a}ren MM-Zellen, w{\"a}hrend MYC erst in extramedull{\"a}rem MM-Tumormaterial verst{\"a}rkt mit der hohen YB 1-Expression korreliert. Die funktionellen Analysen der Arbeit haben gezeigt, dass YB 1 f{\"u}r die Translation der TCTP- und MYC-mRNA essentiell ist. Es kontrolliert die Verteilung dieser mRNAs zwischen translationell aktiven und inaktiven messenger Ribonukleoprotein-Partikeln. Die shRNA-vermittelte Reduktion von YB-1 f{\"u}hrte zur Hemmung der TCTP- und MYC-Translation in der Phase der Initiation. Um den Einfluss der Kandidaten auf das {\"U}berleben der HMZL zu untersuchen, wurden proteinspezifische Knockdown-Experimente durchgef{\"u}hrt. Beim shRNA-vermittelten TCTP-Knockdown konnten keine Auswirkungen auf die Proliferation oder Viabilit{\"a}t von MM-Zellen beobachtet werden. Im Gegensatz dazu ist MYC f{\"u}r das {\"U}berleben und Wachstum der HMZL ausschlaggebend, denn der MYC-Knockdown induzierte Apoptose. Wie beim YB 1-Knockdown war ein Anstieg der Caspase-Aktivit{\"a}t und der Zusammenbruch des mitochondrialen Membranpotentials in den HMZL nachweisbar. Da es beim MYC-Knockdown gleichzeitig zur einer Reduktion der YB 1-Protein- und mRNA-Expression kam, wurde der Einfluss von MYC auf die Transkription des YB-1-Gens untersucht. Mit Hilfe von embryonalen Mausfibroblasten, die ein induzierbares MYC als Transgen besitzen, konnte gezeigt werden, dass die Aktivierung von MYC mit einer Zunahme der YB-1-mRNA einher geht. YB-1 ist somit ein direktes Zielgen des Transkriptionsfaktors MYC. Die Ergebnisse der vorliegenden Arbeit haben zum ersten Mal ein gegenseitiges regulatorisches Netzwerk aufgezeigt, in dem YB 1 transkriptionell durch MYC reguliert wird und YB-1 f{\"u}r die Translation der MYC-mRNA essentiell ist. Die Ko-Expression beider Proteine tr{\"a}gt zum Wachstum und {\"U}berleben von malignen Plasmazellen bei.},
  subject      = {Plasmozytom},
  language  = {de}
}
@article{GassenBrechtefeldSchandryetal.2012,
  author    = {Gassen, Alwine and Brechtefeld, Doris and Schandry, Niklas and Arteaga-Salas, J. Manuel and Israel, Lars and Imhof, Axel and Janzen, Christian J.},
  title     = {DOT1A-dependent H3K76 methylation is required for replication regulation in Trypanosoma brucei},
  series = {Nucleic Acids Research},
  volume    = {40},
  journal   = {Nucleic Acids Research},
  number    = {20},
  doi       = {10.1093/nar/gks801},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-131449},
  pages     = {10302 - 10311},
  year      = {2012},
  abstract  = {Cell-cycle progression requires careful regulation to ensure accurate propagation of genetic material to the daughter cells. Although many cell-cycle regulators are evolutionarily conserved in the protozoan parasite Trypanosoma brucei, novel regulatory mechanisms seem to have evolved. Here, we analyse the function of the histone methyltransferase DOT1A during cell-cycle progression. Over-expression of DOT1A generates a population of cells with aneuploid nuclei as well as enucleated cells. Detailed analysis shows that DOT1A over-expression causes continuous replication of the nuclear DNA. In contrast, depletion of DOT1A by RNAi abolishes replication but does not prevent karyokinesis. As histone H3K76 methylation has never been associated with replication control in eukaryotes before, we have discovered a novel function of DOT1 enzymes, which might not be unique to trypanosomes.},
  language  = {en}
}
@article{NaseemDandekar2012,
  author    = {Naseem, Muhammad and Dandekar, Thomas},
  title     = {The Role of Auxin-Cytokinin Antagonism in Plant-Pathogen Interactions},
  series = {PLOS Pathogens},
  volume    = {8},
  journal   = {PLOS Pathogens},
  number    = {11},
  doi       = {10.1371/journal.ppat.1003026},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-131901},
  pages     = {e1003026},
  year      = {2012},
  abstract  = {No abstract available.},
  language  = {en}
}
@article{MaudetSourisceDraginetal.2013,
  author    = {Maudet, Claire and Sourisce, Ad{\`e}le and Dragin, Lo{\"i}c and Lahouassa, Hichem and Rain, Jean-Christopher and Bouaziz, Serge and Ramirez, Bertha C{\´e}cilia and Margottin-Goguet, Florence},
  title     = {HIV-1 Vpr Induces the Degradation of ZIP and sZIP, Adaptors of the NuRD Chromatin Remodeling Complex, by Hijacking DCAF1/VprBP},
  series = {PLOS ONE},
  volume    = {8},
  journal   = {PLOS ONE},
  number    = {10},
  issn      = {1932-6203},
  doi       = {10.1371/journal.pone.0077320},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-128316},
  pages     = {e77320},
  year      = {2013},
  abstract  = {The Vpr protein from type 1 and type 2 Human Immunodeficiency Viruses (HIV-1 and HIV-2) is thought to inactivate several host proteins through the hijacking of the DCAF1 adaptor of the Cul4A ubiquitin ligase. Here, we identified two transcriptional regulators, ZIP and sZIP, as Vpr-binding proteins degraded in the presence of Vpr. ZIP and sZIP have been shown to act through the recruitment of the NuRD chromatin remodeling complex. Strikingly, chromatin is the only cellular fraction where Vpr is present together with Cul4A ubiquitin ligase subunits. Components of the NuRD complex and exogenous ZIP and sZIP were also associated with this fraction. Several lines of evidence indicate that Vpr induces ZIP and sZIP degradation by hijacking DCAF1: (i) Vpr induced a drastic decrease of exogenously expressed ZIP and sZIP in a dose-dependent manner, (ii) this decrease relied on the proteasome activity, (iii) ZIP or sZIP degradation was impaired in the presence of a DCAF1-binding deficient Vpr mutant or when DCAF1 expression was silenced. Vpr-mediated ZIP and sZIP degradation did not correlate with the growth-related Vpr activities, namely G2 arrest and G2 arrest-independent cytotoxicity. Nonetheless, infection with HIV-1 viruses expressing Vpr led to the degradation of the two proteins. Altogether our results highlight the existence of two host transcription factors inactivated by Vpr. The role of Vpr-mediated ZIP and sZIP degradation in the HIV-1 replication cycle remains to be deciphered.},
  language  = {en}
}
@article{GroenewegvanRoyenFenzetal.2014,
  author    = {Groeneweg, Femke L. and van Royen, Martin E. and Fenz, Susanne and Keizer, Veer I. P. and Geverts, Bart and Prins, Jurrien and de Kloet, E. Ron and Houtsmuller, Adriaan B. and Schmidt, Thomas S. and Schaaf, Marcel J. M.},
  title     = {Quantitation of Glucocorticoid Receptor DNA-Binding Dynamics by Single-Molecule Microscopy and FRAP},
  series = {PLOS ONE},
  volume    = {9},
  journal   = {PLOS ONE},
  number    = {3},
  doi       = {10.1371/journal.pone.0090532},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-117085},
  pages     = {e90532},
  year      = {2014},
  abstract  = {Recent advances in live cell imaging have provided a wealth of data on the dynamics of transcription factors. However, a consistent quantitative description of these dynamics, explaining how transcription factors find their target sequences in the vast amount of DNA inside the nucleus, is still lacking. In the present study, we have combined two quantitative imaging methods, single-molecule microscopy and fluorescence recovery after photobleaching, to determine the mobility pattern of the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR), two ligand-activated transcription factors. For dexamethasone-activated GR, both techniques showed that approximately half of the population is freely diffusing, while the remaining population is bound to DNA. Of this DNA-bound population about half the GRs appeared to be bound for short periods of time (similar to 0.7 s) and the other half for longer time periods (similar to 2.3 s). A similar pattern of mobility was seen for the MR activated by aldosterone. Inactive receptors (mutant or antagonist-bound receptors) show a decreased DNA binding frequency and duration, but also a higher mobility for the diffusing population. Likely, very brief (<= 1 ms) interactions with DNA induced by the agonists underlie this difference in diffusion behavior. Surprisingly, different agonists also induce different mobilities of both receptors, presumably due to differences in ligand-induced conformational changes and receptor complex formation. In summary, our data provide a consistent quantitative model of the dynamics of GR and MR, indicating three types of interactions with DNA, which fit into a model in which frequent low-affinity DNA binding facilitates the search for high-affinity target sequences.},
  language  = {en}
}
@article{SerflingRudolfBuschetal.2014,
  author    = {Serfling, Edgar and Rudolf, Ronald and Busch, Rhoda and Patra, Amiya K. and Muhammad, Khalid and Avots, Andris and Andrau, Jean-Christophe and Klein-Hessling, Stefan},
  title     = {Architecture and expression of the Nfatc1 gene in lymphocytes},
  doi       = {10.3389/fimmu.2014.00021},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-112718},
  year      = {2014},
  abstract  = {In lymphocytes, the three NFAT factors NFATc1 (also designated as NFAT2), NFATc2 (NFAT1), and NFATc3 (NFAT4 or NFATx) are expressed and are the targets of immune receptor signals, which lead to a rapid rise of intracellular Ca++, the activation of phosphatase calcineurin, and to the activation of cytosolic NFATc proteins. In addition to rapid activation of NFAT factors, immune receptor signals lead to accumulation of the short NFATc1/αA isoform in lymphocytes which controls their proliferation and survival. In this mini-review, we summarize our current knowledge on the structure and transcription of the Nfatc1 gene in lymphocytes, which is controlled by two promoters, two poly A addition sites and a remote downstream enhancer. The Nfatc1 gene resembles numerous primary response genes (PRGs) induced by LPS in macrophages. Similar to the PRG promoters, the Nfatc1 promoter region is organized in CpG islands, forms DNase I hypersensitive sites, and is marked by histone tail modifications before induction. By studying gene induction in lymphocytes in detail, it will be important to elucidate whether the properties of the Nfatc1 induction are not only typical for the Nfatc1 gene but also for other transcription factor genes expressed in lymphocytes.},
  language  = {en}
}
@article{ElkonLoayzaPuchKorkmazetal.2015,
  author    = {Elkon, Ran and Loayza-Puch, Fabricio and Korkmaz, Gozde and Lopes, Rui and van Breugel, Pieter C and Bleijerveld, Onno B and Altelaar, AF Maarten and Wolf, Elmar and Lorenzin, Francesca and Eilers, Martin and Agami, Reuven},
  title     = {Myc coordinates transcription and translation to enhance transformation and suppress invasiveness},
  series = {EMBO reports},
  volume    = {16},
  journal   = {EMBO reports},
  number    = {12},
  doi       = {10.15252/embr.201540717},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-150373},
  pages     = {1723-1736},
  year      = {2015},
  abstract  = {c-Myc is one of the major human proto-oncogenes and is often associated with tumor aggression and poor clinical outcome. Paradoxically, Myc was also reported as a suppressor of cell motility, invasiveness, and metastasis. Among the direct targets of Myc are many components of the protein synthesis machinery whose induction results in an overall increase in protein synthesis that empowers tumor cell growth. At present, it is largely unknown whether beyond the global enhancement of protein synthesis, Myc activation results in translation modulation of specific genes. Here, we measured Myc-induced global changes in gene expression at the transcription, translation, and protein levels and uncovered extensive transcript-specific regulation of protein translation. Particularly, we detected a broad coordination between regulation of transcription and translation upon modulation of Myc activity and showed the connection of these responses to mTOR signaling to enhance oncogenic transformation and to the TGFβ pathway to modulate cell migration and invasiveness. Our results elucidate novel facets of Myc-induced cellular responses and provide a more comprehensive view of the consequences of its activation in cancer cells.},
  language  = {en}
}
@article{DembekBarquistBoinettetal.2015,
  author    = {Dembek, Marcin and Barquist, Lars and Boinett, Christine J. and Cain, Amy K. and Mayho, Matthew and Lawley, Trevor D. and Fairweather, Neil F. and Fagan, Robert P.},
  title     = {High-throughput analysis of gene essentiality and sporulation in Clostridium difficile},
  series = {mBio},
  volume    = {6},
  journal   = {mBio},
  number    = {2},
  doi       = {10.1128/mBio.02383-14},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-143745},
  pages     = {e02383-14},
  year      = {2015},
  abstract  = {Clostridium difficile is the most common cause of antibiotic-associated intestinal infections and a significant cause of morbidity and mortality. Infection with C. difficile requires disruption of the intestinal microbiota, most commonly by antibiotic usage. Therapeutic intervention largely relies on a small number of broad-spectrum antibiotics, which further exacerbate intestinal dysbiosis and leave the patient acutely sensitive to reinfection. Development of novel targeted therapeutic interventions will require a detailed knowledge of essential cellular processes, which represent attractive targets, and species-specific processes, such as bacterial sporulation. Our knowledge of the genetic basis of C. difficile infection has been hampered by a lack of genetic tools, although recent developments have made some headway in addressing this limitation. Here we describe the development of a method for rapidly generating large numbers of transposon mutants in clinically important strains of C. difficile. We validated our transposon mutagenesis approach in a model strain of C. difficile and then generated a comprehensive transposon library in the highly virulent epidemic strain R20291 (027/BI/NAP1) containing more than 70,000 unique mutants. Using transposon-directed insertion site sequencing (TraDIS), we have identified a core set of 404 essential genes, required for growth in vitro. We then applied this technique to the process of sporulation, an absolute requirement for C. difficile transmission and pathogenesis, identifying 798 genes that are likely to impact spore production. The data generated in this study will form a valuable resource for the community and inform future research on this important human pathogen.},
  language  = {en}
}
@article{PattschullWalzGruendletal.2019,
  author    = {Pattschull, Grit and Walz, Susanne and Gr{\"u}ndl, Marco and Schwab, Melissa and R{\"u}hl, Eva and Baluapuri, Apoorva and Cindric-Vranesic, Anita and Kneitz, Susanne and Wolf, Elmar and Ade, Carsten P. and Rosenwald, Andreas and von Eyss, Bj{\"o}rn and Gaubatz, Stefan},
  title     = {The Myb-MuvB complex is required for YAP-dependent transcription of mitotic genes},
  series = {Cell Reports},
  volume    = {27},
  journal   = {Cell Reports},
  number    = {12},
  doi       = {10.1016/j.celrep.2019.05.071},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-202039},
  pages     = {3533-3546},
  year      = {2019},
  abstract  = {YAP and TAZ, downstream effectors of the Hippo pathway, are important regulators of proliferation. Here, we show that the ability of YAP to activate mitotic gene expression is dependent on the Myb-MuvB (MMB) complex, a master regulator of genes expressed in the G2/M phase of the cell cycle. By carrying out genome-wide expression and binding analyses, we found that YAP promotes binding of the MMB subunit B-MYB to the promoters of mitotic target genes. YAP binds to B-MYB and stimulates B-MYB chromatin association through distal enhancer elements that interact with MMB-regulated promoters through chromatin looping. The cooperation between YAP and B-MYB is critical for YAP-mediated entry into mitosis. Furthermore, the expression of genes coactivated by YAP and B-MYB is associated with poor survival of cancer patients. Our findings provide a molecular mechanism by which YAP and MMB regulate mitotic gene expression and suggest a link between two cancer-relevant signaling pathways.},
  language  = {en}
}
@article{HennigDjakovicDoelkenetal.2021,
  author    = {Hennig, Thomas and Djakovic, Lara and D{\"o}lken, Lars and Whisnant, Adam W.},
  title     = {A Review of the Multipronged Attack of Herpes Simplex Virus 1 on the Host Transcriptional Machinery},
  series = {Viruses},
  volume    = {13},
  journal   = {Viruses},
  number    = {9},
  issn      = {1999-4915},
  doi       = {10.3390/v13091836},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-246165},
  year      = {2021},
  abstract  = {During lytic infection, herpes simplex virus (HSV) 1 induces a rapid shutoff of host RNA synthesis while redirecting transcriptional machinery to viral genes. In addition to being a major human pathogen, there is burgeoning clinical interest in HSV as a vector in gene delivery and oncolytic therapies, necessitating research into transcriptional control. This review summarizes the array of impacts that HSV has on RNA Polymerase (Pol) II, which transcribes all mRNA in infected cells. We discuss alterations in Pol II holoenzymes, post-translational modifications, and how viral proteins regulate specific activities such as promoter-proximal pausing, splicing, histone repositioning, and termination with respect to host genes. Recent technological innovations that have reshaped our understanding of previous observations are summarized in detail, along with specific research directions and technical considerations for future studies.},
  language  = {en}
}
@article{WenckerMarincolaSchoenfelderetal.2021,
  author    = {Wencker, Freya D. R and Marincola, Gabriella and Schoenfelder, Sonja M. K. and Maaß, Sandra and Becher, D{\"o}rte and Ziebuhr, Wilma},
  title     = {Another layer of complexity in Staphylococcus aureus methionine biosynthesis control: unusual RNase III-driven T-box riboswitch cleavage determines met operon mRNA stability and decay},
  series = {Nucleic Acids Research},
  volume    = {49},
  journal   = {Nucleic Acids Research},
  number    = {4},
  doi       = {10.1093/nar/gkaa1277},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-259029},
  pages     = {2192-2212},
  year      = {2021},
  abstract  = {In Staphylococcus aureus, de novo methionine biosynthesis is regulated by a unique hierarchical pathway involving stringent-response controlled CodY repression in combination with a T-box riboswitch and RNA decay. The T-box riboswitch residing in the 5′ untranslated region (met leader RNA) of the S. aureus metICFE-mdh operon controls downstream gene transcription upon interaction with uncharged methionyl-tRNA. met leader and metICFE-mdh (m)RNAs undergo RNase-mediated degradation in a process whose molecular details are poorly understood. Here we determined the secondary structure of the met leader RNA and found the element to harbor, beyond other conserved T-box riboswitch structural features, a terminator helix which is target for RNase III endoribonucleolytic cleavage. As the terminator is a thermodynamically highly stable structure, it also forms posttranscriptionally in met leader/ metICFE-mdh read-through transcripts. Cleavage by RNase III releases the met leader from metICFE-mdh mRNA and initiates RNase J-mediated degradation of the mRNA from the 5′-end. Of note, metICFE-mdh mRNA stability varies over the length of the transcript with a longer lifespan towards the 3′-end. The obtained data suggest that coordinated RNA decay represents another checkpoint in a complex regulatory network that adjusts costly methionine biosynthesis to current metabolic requirements.},
  language  = {en}
}
@phdthesis{FetivaMora2023,
  author    = {Fetiva Mora, Maria Camila},
  title     = {Changes in chromatin accessibility by oncogenic YAP and its relevance for regulation of cell cycle gene expression and cell migration},
  doi       = {10.25972/OPUS-30291},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-302910},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2023},
  abstract  = {Various types of cancer involve aberrant cell cycle regulation. Among the pathways responsible for tumor growth, the YAP oncogene, a key downstream effector of the Hippo pathway, is responsible for oncogenic processes including cell proliferation, and metastasis by controlling the expression of cell cycle genes. In turn, the MMB multiprotein complex (which is formed when B-MYB binds to the MuvB core) is a master regulator of mitotic gene expression, which has also been associated with cancer. Previously, our laboratory identified a novel crosstalk between the MMB-complex and YAP. By binding to enhancers of MMB target genes and promoting B-MYB binding to promoters, YAP and MMB co-regulate a set of mitotic and cytokinetic target genes which promote cell proliferation. This doctoral thesis addresses the mechanisms of YAP and MMB mediated transcription, and it characterizes the role of YAP regulated enhancers in transcription of cell cycle genes. The results reported in this thesis indicate that expression of constitutively active, oncogenic YAP5SA leads to widespread changes in chromatin accessibility in untransformed human MCF10A cells. ATAC-seq identified that newly accessible and active regions include YAP-bound enhancers, while the MMB-bound promoters were found to be already accessible and remain open during YAP induction. By means of CRISPR-interference (CRISPRi) and chromatin immuniprecipitation (ChIP), we identified a role of YAP-bound enhancers in recruitment of CDK7 to MMB-regulated promoters and in RNA Pol II driven transcriptional initiation and elongation of G2/M genes. Moreover, by interfering with the YAP-B-MYB protein interaction, we can show that binding of YAP to B-MYB is also critical for the initiation of transcription at MMB-regulated genes. Unexpectedly, overexpression of YAP5SA also leads to less accessible chromatin regions or chromatin closing. Motif analysis revealed that the newly closed regions contain binding motifs for the p53 family of transcription factors. Interestingly, chromatin closing by YAP is linked to the reduced expression and loss of chromatin-binding of the p53 family member Np63. Furthermore, I demonstrate that downregulation of Np63 following expression of YAP is a key step in driving cellular migration. Together, the findings of this thesis provide insights into the role of YAP in the chromatin changes that contribute to the oncogenic activities of YAP. The overexpression of YAP5SA not only leads to the opening of chromatin at YAP-bound enhancers which together with the MMB complex stimulate the expression of G2/M genes, but also promotes the closing of chromatin at ∆Np63 -bound regions in order to lead to cell migration.},
  subject      = {Chromatin},
  language  = {en}
}
@article{DjakovicHennigReinischetal.2023,
  author    = {Djakovic, Lara and Hennig, Thomas and Reinisch, Katharina and Milić, Andrea and Whisnant, Adam W. and Wolf, Katharina and Weiß, Elena and Haas, Tobias and Grothey, Arnhild and J{\"u}rges, Christopher S. and Kluge, Michael and Wolf, Elmar and Erhard, Florian and Friedel, Caroline C. and D{\"o}lken, Lars},
  title     = {The HSV-1 ICP22 protein selectively impairs histone repositioning upon Pol II transcription downstream of genes},
  series = {Nature Communications},
  volume    = {14},
  journal   = {Nature Communications},
  doi       = {10.1038/s41467-023-40217-w},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-358161},
  year      = {2023},
  abstract  = {Herpes simplex virus 1 (HSV-1) infection and stress responses disrupt transcription termination by RNA Polymerase II (Pol II). In HSV-1 infection, but not upon salt or heat stress, this is accompanied by a dramatic increase in chromatin accessibility downstream of genes. Here, we show that the HSV-1 immediate-early protein ICP22 is both necessary and sufficient to induce downstream open chromatin regions (dOCRs) when transcription termination is disrupted by the viral ICP27 protein. This is accompanied by a marked ICP22-dependent loss of histones downstream of affected genes consistent with impaired histone repositioning in the wake of Pol II. Efficient knock-down of the ICP22-interacting histone chaperone FACT is not sufficient to induce dOCRs in ΔICP22 infection but increases dOCR induction in wild-type HSV-1 infection. Interestingly, this is accompanied by a marked increase in chromatin accessibility within gene bodies. We propose a model in which allosteric changes in Pol II composition downstream of genes and ICP22-mediated interference with FACT activity explain the differential impairment of histone repositioning downstream of genes in the wake of Pol II in HSV-1 infection.},
  language  = {en}
}