{"id":{"repo_id":"bayreuth","oai_identifier":"oai:epub.uni-bayreuth.de:1736"},"canonical_url":"https://search.dev.ndltd.org/etd/bayreuth/oai:epub.uni-bayreuth.de:1736","repository":{"repo_id":"bayreuth","name":"Universität Bayreuth","base_url":"https://epub.uni-bayreuth.de/cgi/oai2"},"display":{"title":"Enhanced protein degradation by branched ubiquitin chains","abstract":"Posttranslational modification of cell cycle regulators with ubiquitin chains is essential for eukaryotic cell division. Such chains can be connected through seven lysine residues or the amino-terminus of ubiquitin, thereby allowing the assembly of eight homogenous and multiple mixed or branched conjugates. While functions of homogenous chain types have been described, physiological roles of branched structures are unknown. The anaphase-promoting complex (APC/C) catalyzes degradation of key regulators during the cell cycle causing proper transition through the cell cycle. Here, I report that the APC/C efficiently synthesizes substrate-attached branched conjugates and enhances recognition of ubiquitylated substrates by the proteasome, thereby driving the degradation of cell cycle regulators during early mitosis. I showed several APC/C-substrates require the ubiquitin-conjugating enzyme E2 S (Ube2S) for degradation, e.g. the Never in mitosis A-related kinase 2 (Nek2A). The reconstitution of Nek2A ubiquitylation revealed that Ube2S does not simply extend a conjugate, but instead branches multiple lysine11-linked chains off the ubiquitin chains produced by the ubiquitin-conjugating enzyme E2 C (Ube2C). Therefore, I identified an enzyme and substrates for modification with branched ubiquitin chains, which points to an important role of these conjugates in providing an improved signal for proteasomal degradation. Compared to homogenous chains, branched conjugates synthesized by the APC/C increase the efficiency of proteasomal substrate recognition, and accordingly, are required for the degradation of cell cycle regulators at times of limited APC/C activity such as prometaphase. Hence, the APC/C is an enzyme that synthesizes branched ubiquitin chains, which provide an improved signal for proteasomal degradation.","abstract_html":"Posttranslational modification of cell cycle regulators with ubiquitin chains is essential for eukaryotic cell division. Such chains can be connected through seven lysine residues or the amino-terminus of ubiquitin, thereby allowing the assembly of eight homogenous and multiple mixed or branched conjugates. While functions of homogenous chain types have been described, physiological roles of branched structures are unknown. The anaphase-promoting complex (APC/C) catalyzes degradation of key regulators during the cell cycle causing proper transition through the cell cycle. Here, I report that the APC/C efficiently synthesizes substrate-attached branched conjugates and enhances recognition of ubiquitylated substrates by the proteasome, thereby driving the degradation of cell cycle regulators during early mitosis. I showed several APC/C-substrates require the ubiquitin-conjugating enzyme E2 S (Ube2S) for degradation, e.g. the Never in mitosis A-related kinase 2 (Nek2A). The reconstitution of Nek2A ubiquitylation revealed that Ube2S does not simply extend a conjugate, but instead branches multiple lysine11-linked chains off the ubiquitin chains produced by the ubiquitin-conjugating enzyme E2 C (Ube2C). Therefore, I identified an enzyme and substrates for modification with branched ubiquitin chains, which points to an important role of these conjugates in providing an improved signal for proteasomal degradation. Compared to homogenous chains, branched conjugates synthesized by the APC/C increase the efficiency of proteasomal substrate recognition, and accordingly, are required for the degradation of cell cycle regulators at times of limited APC/C activity such as prometaphase. Hence, the APC/C is an enzyme that synthesizes branched ubiquitin chains, which provide an improved signal for proteasomal degradation.","abstract_has_math":false,"creators":["Meyer, Hermann-Josef"],"institution":"Universität Bayreuth","degree_name":null,"degree_level":"thesis.doctoral","degree_discipline":null,"degree_department":null,"school":null,"contributors":["Stemmann, Olaf"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2014,"date_issued":"2014-08-04","date_published":"2014-08-04","updated_at":"2026-07-27T18:49:36Z","subjects":[],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://epub.uni-bayreuth.de/id/eprint/1736/","outbound_label":"Repository record","outbound_source":"source_url"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Stemmann, Olaf"]},{"key":"dc:creator","label":"Author","values":["Meyer, Hermann-Josef"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:publisher","label":"Institution","values":["Universität Bayreuth"]},{"key":"dc:type","label":"Dc Type","values":["doctoralThesis"]},{"key":"thesis:degree_level","label":"Degree Level","values":["thesis.doctoral"]},{"key":"thesis:institution_name","label":"Thesis Institution Name","values":["Universität Bayreuth"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Posttranslational modification of cell cycle regulators with ubiquitin chains is essential for eukaryotic cell division. Such chains can be connected through seven lysine residues or the amino-terminus of ubiquitin, thereby allowing the assembly of eight homogenous and multiple mixed or branched conjugates. While functions of homogenous chain types have been described, physiological roles of branched structures are unknown. The anaphase-promoting complex (APC/C) catalyzes degradation of key regulators during the cell cycle causing proper transition through the cell cycle. Here, I report that the APC/C efficiently synthesizes substrate-attached branched conjugates and enhances recognition of ubiquitylated substrates by the proteasome, thereby driving the degradation of cell cycle regulators during early mitosis. I showed several APC/C-substrates require the ubiquitin-conjugating enzyme E2 S (Ube2S) for degradation, e.g. the Never in mitosis A-related kinase 2 (Nek2A). The reconstitution of Nek2A ubiquitylation revealed that Ube2S does not simply extend a conjugate, but instead branches multiple lysine11-linked chains off the ubiquitin chains produced by the ubiquitin-conjugating enzyme E2 C (Ube2C). Therefore, I identified an enzyme and substrates for modification with branched ubiquitin chains, which points to an important role of these conjugates in providing an improved signal for proteasomal degradation. Compared to homogenous chains, branched conjugates synthesized by the APC/C increase the efficiency of proteasomal substrate recognition, and accordingly, are required for the degradation of cell cycle regulators at times of limited APC/C activity such as prometaphase. Hence, the APC/C is an enzyme that synthesizes branched ubiquitin chains, which provide an improved signal for proteasomal degradation.","Posttranslationale Modifikation von Regulatoren des Zellzyklus mit Ubiquitinketten ist essentiell für Zellteilung. Diese Ketten können durch sieben verschiedene Lysine oder den Amino-Terminus von Ubiquitin ver-knüpft sein, welches die Formierung von acht homogenen und vielen gemischten oder verzweigten Konjugaten erlaubt. Funktionen für homo-gene Kettenarten sind bereits beschrieben worden, während die physiologische Bedeutung der verzweigten Strukturen unbekannt ist. Der Anaphase fördernde Komplex (APC/C) katalysiert die Degradierung von wichtigen Regulatoren innerhalb des Zellzyklus, was zu einem geordneten Ablauf des Zellzyklus führt. Ich berichte hier, dass der APC/C verzweigte, substratgekoppelte Ubiquitinketten effizient synthetisiert, was die Bindung von ubiquitinierten Substraten durch das Proteasom verstärkt und wodurch der Abbau von Zellzyklusregulatoren in früher Mitose vorangetrieben wird. Ich habe aufgedeckt, dass mehrere APC/C- Substrate das ubiquitinkonjugierende Enzym E2 S (Ube2S) für ihre Degradierung benötigen, z.B. die Niemals in Mitose A verwandte Kinase 2 (Nek2A). Die Rekonstitution der Nek2A-Ubiquitinierung zeigt, dass Ube2S nicht nur ein Konjugat verlängert, sondern stattdessen mehrere Lysin11-geknüpfte Ketten verzweigt, welche von Ubiquitinketten ausgehen, die durch das ubiquitinkonjugierende Enzym E2 C (Ube2C) produziert worden sind. Daher habe ich ein Enzym und Substrate identifiziert, welche mit verzweigten Ketten modifiziert sind, was auf eine wichtige Rolle dieser Konjugate als ein stärkeres Abbausignal hinweist. Verglichen mit homogenen Ketten steigt die Effizienz der vom APC/C-produzierten, verzweigten Ketten im Bezug auf proteasomale Substraterkennung und deshalb sind verzweigte Ubiquitinketten für die Degradierung von Zellzyklusregulatoren zuzeiten limitierter APC/C- Aktivität erforderlich, wie in Prometaphase. Infolgedessen ist der APC/C ein Enzym, das verz-weigte Ubiquitinketten synthetisiert, welche ein verstärktes Abbausignal durch das Proteasom darstellen."]},{"key":"dc:format.medium","label":"Dc Format Medium","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Enhanced protein degradation by branched ubiquitin chains"]}]}],"canonical_facts":{"dc:contributor":["Stemmann, Olaf"],"dc:creator":["Meyer, Hermann-Josef"],"dc:description.abstract":["Posttranslational modification of cell cycle regulators with ubiquitin chains is essential for eukaryotic cell division. Such chains can be connected through seven lysine residues or the amino-terminus of ubiquitin, thereby allowing the assembly of eight homogenous and multiple mixed or branched conjugates. While functions of homogenous chain types have been described, physiological roles of branched structures are unknown. The anaphase-promoting complex (APC/C) catalyzes degradation of key regulators during the cell cycle causing proper transition through the cell cycle. Here, I report that the APC/C efficiently synthesizes substrate-attached branched conjugates and enhances recognition of ubiquitylated substrates by the proteasome, thereby driving the degradation of cell cycle regulators during early mitosis. I showed several APC/C-substrates require the ubiquitin-conjugating enzyme E2 S (Ube2S) for degradation, e.g. the Never in mitosis A-related kinase 2 (Nek2A). The reconstitution of Nek2A ubiquitylation revealed that Ube2S does not simply extend a conjugate, but instead branches multiple lysine11-linked chains off the ubiquitin chains produced by the ubiquitin-conjugating enzyme E2 C (Ube2C). Therefore, I identified an enzyme and substrates for modification with branched ubiquitin chains, which points to an important role of these conjugates in providing an improved signal for proteasomal degradation. Compared to homogenous chains, branched conjugates synthesized by the APC/C increase the efficiency of proteasomal substrate recognition, and accordingly, are required for the degradation of cell cycle regulators at times of limited APC/C activity such as prometaphase. Hence, the APC/C is an enzyme that synthesizes branched ubiquitin chains, which provide an improved signal for proteasomal degradation.","Posttranslationale Modifikation von Regulatoren des Zellzyklus mit Ubiquitinketten ist essentiell für Zellteilung. Diese Ketten können durch sieben verschiedene Lysine oder den Amino-Terminus von Ubiquitin ver-knüpft sein, welches die Formierung von acht homogenen und vielen gemischten oder verzweigten Konjugaten erlaubt. Funktionen für homo-gene Kettenarten sind bereits beschrieben worden, während die physiologische Bedeutung der verzweigten Strukturen unbekannt ist. Der Anaphase fördernde Komplex (APC/C) katalysiert die Degradierung von wichtigen Regulatoren innerhalb des Zellzyklus, was zu einem geordneten Ablauf des Zellzyklus führt. Ich berichte hier, dass der APC/C verzweigte, substratgekoppelte Ubiquitinketten effizient synthetisiert, was die Bindung von ubiquitinierten Substraten durch das Proteasom verstärkt und wodurch der Abbau von Zellzyklusregulatoren in früher Mitose vorangetrieben wird. Ich habe aufgedeckt, dass mehrere APC/C- Substrate das ubiquitinkonjugierende Enzym E2 S (Ube2S) für ihre Degradierung benötigen, z.B. die Niemals in Mitose A verwandte Kinase 2 (Nek2A). Die Rekonstitution der Nek2A-Ubiquitinierung zeigt, dass Ube2S nicht nur ein Konjugat verlängert, sondern stattdessen mehrere Lysin11-geknüpfte Ketten verzweigt, welche von Ubiquitinketten ausgehen, die durch das ubiquitinkonjugierende Enzym E2 C (Ube2C) produziert worden sind. Daher habe ich ein Enzym und Substrate identifiziert, welche mit verzweigten Ketten modifiziert sind, was auf eine wichtige Rolle dieser Konjugate als ein stärkeres Abbausignal hinweist. Verglichen mit homogenen Ketten steigt die Effizienz der vom APC/C-produzierten, verzweigten Ketten im Bezug auf proteasomale Substraterkennung und deshalb sind verzweigte Ubiquitinketten für die Degradierung von Zellzyklusregulatoren zuzeiten limitierter APC/C- Aktivität erforderlich, wie in Prometaphase. Infolgedessen ist der APC/C ein Enzym, das verz-weigte Ubiquitinketten synthetisiert, welche ein verstärktes Abbausignal durch das Proteasom darstellen."],"dc:format.medium":["application/pdf"],"dc:publisher":["Universität Bayreuth"],"dc:title":["Enhanced protein degradation by branched ubiquitin chains"],"dc:type":["doctoralThesis"],"thesis:degree_level":["thesis.doctoral"],"thesis:institution_name":["Universität Bayreuth"]},"updated_at":"2026-07-27T18:49:36Z"}