Das Protoonkogen c-myc kodiert für den Transkriptionsfaktor cMyc, der als Heterodimer mit Max die Transkription von Zielgenen aktiviert und als ternärer Komplex mit Max und Miz1 die Transkription einer zweiten Klasse von Zielgenen reprimiert. In dieser Arbeit wird gezeigt, dass HectH9, eine Ubiquitin E3 Ligase, endogen sowohl an cMyc als auch an Miz1 bindet. Miz1 wird im Gegensatz cMyc nicht von HectH9 modifiziert, kann aber die Ubiquitiniung von cMyc durch HectH9 inhibieren. Die Ubiquitinketten die HectH9 auf cMyc synthetisiert, sind über Lysin 63 verknüpft. Diese Modifikation führt nicht zu beschleunigtem Abbau von cMyc, sondern verändert dessen biologische Eigenschaften. Die Depletion von HectH9 durch shRNA reduziert die Fähigkeit von cMyc, Zielgene zu aktivieren. Die Repression von cMyc Zielgenen bleibt jedoch unbeeinflusst. Diese Ergebnisse lassen sich in Experimenten mit Myc KR6, einer cMyc Mu- tante die nicht mehr von HectH9 ubiquitiniert werden kann, bestätigen. Die Aktivierungsdefizienz von Myc KR6 zeigt sich in einer FACS-Analyse durch fehlende Induktion von Zellteilung und Apoptose. Während wildtyp cMyc bei gehungerten 3T3 Zellen Zellzyklusprogression und Zelltot induziert, verhalten sich Myc KR6 infizierte Zellen vergleichbar zu Kontrollzellen. Die Ursache hier für liegt in der Notwendigkeit der Ubiquitinierung von cMyc für die Rekrutierung von p300 an cMyc aktivierte Promotoren. Obwohl wildtyp cMyc und Myc KR6 gleich effizient an Zielpromotoren assoziieren, kann lediglich wildtyp cMyc die Histonacetyltransferase p300 binden, welche notwendig für Rekrutierung von generellen Transkriptionsfaktoren ist. TopBP1 ist Bestandteil der DNA Schadenssignalkaskade und essentieller Aktiva- tor von ATR nach DNA Schadensinduktion durch UV-B Strahlung. Zellen, die Miz1 überexprimieren zeigen Anzeichen von DNA Schaden und weisen verlän- gerte Halbwertszeiten von TopBP1 und ATR auf. In dieser Arbeit konnte gezeigt werden, dass die Überexpression von HectH9 die Halbwertszeit von TopBP1 nach UV-B Strahlung im Vergleich zu Kontrollzellen reduziert und TopBP1 von HectH9 mit über Lysin 48 verknüpfte Polyubiquitinketten markiert wird. Diese Polyubiquitinierung wird von Miz1 gehemmt. Eine TopBP1 Mutante, die Miz1 nicht mehr binden kann, wird gegenüber wildtyp TopBP1 stärker ubiquitiniert und schneller abgebaut. Zusammenfassend wird deutlich, dass die E3 Ligase HectH9 entscheidend denZellzyklus vorantreibt, in dem sie durch Ubiquitinierung über Lysin 63 cMyc aktiviert und so die Zellzyklusprogression fördert und zusätzlich über Abbau von TopBP1 die Induktion von Zellzyklusarest reduziert. Diese onkogenen Ei- genschaften werden besonders im Kolonkarzinom deutlich. Während in normalen Darmgewebe HectH9 mRNA in nur 10% aller untersuchten Proben schwach nachzuweisen ist, ist in 80% aller untersuchten Adenokarzinome die HectH9 Transkription erhöht. Miz1 Hock, Andreas Kurt Hock Andreas Kurt doctoralThesis Characterisation of the E3 ligase HectH9 and its influence on cMyc and TopBP1 TopBP1 opus:3713 ths Prof. Dr. Eilers Martin Eilers, Martin (Prof. Dr.) 2011-06-28 https://archiv.ub.uni-marburg.de/diss/z2011/0351/cover.png Ubiquitin monograph cMyc 2010-09-10 Miz1 The proto-oncogene c-myc encodes for the transcription factor cMyc, which acti- vates expression of target genes in a heterodimer with Max, and acts as a repressor in a ternary complex with Max and Miz1. In this work I show that the E3 ligase HectH9 interacts with both Miz1 and cMyc. Unlike cMyc, Miz1 is not ubiquitina- ted by HectH9 but acts as an inhibitor of cMyc ubiquitination by HectH9. This polyubiquitination is inter-linked via Lysine 63 and does not lead to increased degradation of cMyc, but alters its biological properties: Depletion of HectH9 by shRNA leads to reduced induction of cMyc target genes, while repression of cMyc target genes is unaltered. These experiments are supported by experiments with Myc KR6, a cMyc mutant which can not be ubiquitinated by HectH9: Myc KR6 fails to induce cell cycle progression and apoptosis in comparison to wild type cMyc in starved 3T3 fibroblasts. One cause for this lies in the inability of Myc KR6 to interact with the histone acetyltransferase p300: While both, wild type cMyc and Myc KR6 bind similarly to Myc target promoters, only wild type cMyc is capable of recruiting p300 which is needed for efficient binding of general transcription factors. TopBP1 is an essential activator of ATR after DNA damage induction by UV-B exposition. Cells that over-express Miz1 show signs of DNA damage and have increased half life times of TopBP1 and ATR. I could show that over-expression of HectH9 reduces the half life of TopBP1 after DNA damage in comparison to control cells and that HectH9 polyubiquitinates TopBP1 via lysine 48 interlinked chains. This reaction is inhibited by over-expression of Miz1. A TopBP1 mutant, which does not bind to Miz1 anymore, is ubiquitinated stronger by HectH9 than wild type TopBP1. Taken together these results show that HectH9 is an important cell cycle inducer by ubiquitinating and activating cMyc and thereby promoting cell cycle entry and in addition to that reducing DNA damage dependent cell cycle arrest by ubiquitinating and degrading TopBP1. These oncogenic properties are apparent in colon carcinomas: Although in normal colon tissue HectH9 is only detectable in 10% of all samples at a low level, it is highly transcribed in 80% of all analyzed colon carcinoma samples. application/pdf DNA damage Molekularbiologie und Tumorforschung p300 https://doi.org/10.17192/z2011.0351 Philipps-Universität Marburg Natural sciences + mathematics Naturwissenschaften TopBP1 ubiquitin 2010 Medizin cMyc p300 HectH9 Welcker, M. ; Orian, A. ; Grim, J. A. ; Eisenman, R. N. ; Clurman, XXIX Literaturverzeichnis B. 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