Hillen, Hauke S.

[["dc.bibliographiccitation.issue","11"],["dc.bibliographiccitation.journal","Cellular and Molecular Life Sciences"],["dc.bibliographiccitation.volume","79"],["dc.contributor.author","Wohlfarter, Yvonne"],["dc.contributor.author","Eidelpes, Reiner"],["dc.contributor.author","Yu, Ryan D."],["dc.contributor.author","Sailer, Sabrina"],["dc.contributor.author","Koch, Jakob"],["dc.contributor.author","Karall, Daniela"],["dc.contributor.author","Scholl-Bürgi, Sabine"],["dc.contributor.author","Amberger, Albert"],["dc.contributor.author","Hillen, Hauke S."],["dc.contributor.author","Zschocke, Johannes"],["dc.contributor.author","Keller, Markus A."],["dc.date.accessioned","2022-12-01T08:31:40Z"],["dc.date.available","2022-12-01T08:31:40Z"],["dc.date.issued","2022"],["dc.description.abstract","Abstract\r\n Multifunctional proteins are challenging as it can be difficult to confirm pathomechanisms associated with disease-causing genetic variants. The human 17β-hydroxysteroid dehydrogenase 10 (HSD10) is a moonlighting enzyme with at least two structurally and catalytically unrelated functions. HSD10 disease was originally described as a disorder of isoleucine metabolism, but the clinical manifestations were subsequently shown to be linked to impaired mtDNA transcript processing due to deficient function of HSD10 in the mtRNase P complex. A surprisingly large number of other, mostly enzymatic and potentially clinically relevant functions have been attributed to HSD10. Recently, HSD10 was reported to exhibit phospholipase C-like activity towards cardiolipins (CL), important mitochondrial phospholipids. To assess the physiological role of the proposed CL-cleaving function, we studied CL architectures in living cells and patient fibroblasts in different genetic backgrounds and lipid environments using our well-established LC–MS/MS cardiolipidomic pipeline. These experiments revealed no measurable effect on CLs, indicating that HSD10 does not have a physiologically relevant function towards CL metabolism. Evolutionary constraints could explain the broad range of reported substrates for HSD10 in vitro. The combination of an essential structural with a non-essential enzymatic function in the same protein could direct the evolutionary trajectory towards improvement of the former, thereby increasing the flexibility of the binding pocket, which is consistent with the results presented here."],["dc.description.sponsorship"," Austrian Science Fund http://dx.doi.org/10.13039/501100002428"],["dc.description.sponsorship"," Österreichischen Akademie der Wissenschaften http://dx.doi.org/10.13039/501100001822"],["dc.description.sponsorship"," Deutsche Forschungsgemeinschaft http://dx.doi.org/10.13039/501100001659"],["dc.description.sponsorship","Austrian Science Fund"],["dc.identifier.doi","10.1007/s00018-022-04579-6"],["dc.identifier.pii","4579"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/118230"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-621"],["dc.relation.eissn","1420-9071"],["dc.relation.issn","1420-682X"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.title","ost in promiscuity? An evolutionary and biochemical evaluation of HSD10 function in cardiolipin metabolism"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.journal","Nature Structural & Molecular Biology"],["dc.contributor.author","Kabinger, Florian"],["dc.contributor.author","Stiller, Carina"],["dc.contributor.author","Schmitzová, Jana"],["dc.contributor.author","Dienemann, C."],["dc.contributor.author","Kokic, Goran"],["dc.contributor.author","Hillen, Hauke S."],["dc.contributor.author","Höbartner, Claudia"],["dc.contributor.author","Cramer, Patrick"],["dc.date.accessioned","2021-09-01T06:42:22Z"],["dc.date.available","2021-09-01T06:42:22Z"],["dc.date.issued","2021"],["dc.description.abstract","Abstract Molnupiravir is an orally available antiviral drug candidate currently in phase III trials for the treatment of patients with COVID-19. Molnupiravir increases the frequency of viral RNA mutations and impairs SARS-CoV-2 replication in animal models and in humans. Here, we establish the molecular mechanisms underlying molnupiravir-induced RNA mutagenesis by the viral RNA-dependent RNA polymerase (RdRp). Biochemical assays show that the RdRp uses the active form of molnupiravir, β- d - N 4 -hydroxycytidine (NHC) triphosphate, as a substrate instead of cytidine triphosphate or uridine triphosphate. When the RdRp uses the resulting RNA as a template, NHC directs incorporation of either G or A, leading to mutated RNA products. Structural analysis of RdRp–RNA complexes that contain mutagenesis products shows that NHC can form stable base pairs with either G or A in the RdRp active center, explaining how the polymerase escapes proofreading and synthesizes mutated RNA. This two-step mutagenesis mechanism probably applies to various viral polymerases and can explain the broad-spectrum antiviral activity of molnupiravir."],["dc.identifier.doi","10.1038/s41594-021-00651-0"],["dc.identifier.pii","651"],["dc.identifier.pmid","34381216"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/89038"],["dc.identifier.url","https://mbexc.uni-goettingen.de/literature/publications/381"],["dc.identifier.url","https://sfb1190.med.uni-goettingen.de/production/literature/publications/171"],["dc.identifier.url","https://for2848.gwdguser.de/literature/publications/28"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-455"],["dc.relation","EXC 2067: Multiscale Bioimaging"],["dc.relation","SFB 1190: Transportmaschinen und Kontaktstellen zellulärer Kompartimente"],["dc.relation","FOR 2848: Architektur und Heterogenität der inneren mitochondrialen Membran auf der Nanoskala"],["dc.relation","FOR 2848 | St01: Structure and distribution of ribosomes at the inner mitochondrial membrane"],["dc.relation.eissn","1545-9985"],["dc.relation.issn","1545-9993"],["dc.relation.workinggroup","RG Cramer"],["dc.relation.workinggroup","RG Hillen (Structure and Function of Molecular Machines)"],["dc.rights","CC BY 4.0"],["dc.title","Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","965"],["dc.bibliographiccitation.issue","11"],["dc.bibliographiccitation.journal","Trends in Biochemical Sciences"],["dc.bibliographiccitation.lastpage","977"],["dc.bibliographiccitation.volume","47"],["dc.contributor.author","Bhatta, Arjun"],["dc.contributor.author","Hillen, Hauke S."],["dc.date.accessioned","2022-12-01T08:30:44Z"],["dc.date.available","2022-12-01T08:30:44Z"],["dc.date.issued","2022"],["dc.description.sponsorship"," http://dx.doi.org/10.13039/501100001659 Deutsche Forschungsgemeinschaft"],["dc.identifier.doi","10.1016/j.tibs.2022.05.006"],["dc.identifier.pii","S0968000422001396"],["dc.identifier.pmid","35725940"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/117964"],["dc.identifier.url","https://sfb1190.med.uni-goettingen.de/production/literature/publications/177"],["dc.identifier.url","https://mbexc.uni-goettingen.de/literature/publications/507"],["dc.identifier.url","https://for2848.gwdguser.de/literature/publications/33"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-621"],["dc.relation","SFB 1190: Transportmaschinen und Kontaktstellen zellulärer Kompartimente"],["dc.relation","EXC 2067: Multiscale Bioimaging"],["dc.relation","FOR 2848: Architektur und Heterogenität der inneren mitochondrialen Membran auf der Nanoskala"],["dc.relation","FOR 2848 | St01: Structure and distribution of ribosomes at the inner mitochondrial membrane"],["dc.relation.issn","0968-0004"],["dc.relation.workinggroup","RG Hillen (Structure and Function of Molecular Machines)"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://www.elsevier.com/tdm/userlicense/1.0/"],["dc.title","Structural and mechanistic basis of RNA processing by protein-only ribonuclease P enzymes"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","overview_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","1454"],["dc.bibliographiccitation.issue","10"],["dc.bibliographiccitation.journal","Human Mutation"],["dc.bibliographiccitation.lastpage","1471"],["dc.bibliographiccitation.volume","43"],["dc.contributor.affiliation","Bögershausen, Nina; 1\r\nInstitute of Human Genetics\r\nUniversity Medical Center Göttingen\r\nGöttingen Germany"],["dc.contributor.affiliation","Krawczyk, Hannah E.; 1\r\nInstitute of Human Genetics\r\nUniversity Medical Center Göttingen\r\nGöttingen Germany"],["dc.contributor.affiliation","Jamra, Rami A.; 2\r\nInstitute of Human Genetics\r\nUniversity of Leipzig Medical Center\r\nLeipzig Germany"],["dc.contributor.affiliation","Lin, Sheng‐Jia; 3\r\nGenes & Human Disease Research Program\r\nOklahoma Medical Research Foundation\r\nOklahoma City Oklahoma USA"],["dc.contributor.affiliation","Yigit, Gökhan; 1\r\nInstitute of Human Genetics\r\nUniversity Medical Center Göttingen\r\nGöttingen Germany"],["dc.contributor.affiliation","Hüning, Irina; 4\r\nInstitut für Humangenetik\r\nUniversitätsklinikum Schleswig‐Holstein\r\nLübeck Germany"],["dc.contributor.affiliation","Polo, Anna M.; 5\r\nMVZ Labor Krone\r\nFilialpraxis für Humangenetik\r\nBielefeld Germany"],["dc.contributor.affiliation","Vona, Barbara; 1\r\nInstitute of Human Genetics\r\nUniversity Medical Center Göttingen\r\nGöttingen Germany"],["dc.contributor.affiliation","Huang, Kevin; 3\r\nGenes & Human Disease Research Program\r\nOklahoma Medical Research Foundation\r\nOklahoma City Oklahoma USA"],["dc.contributor.affiliation","Schmidt, Julia; 1\r\nInstitute of Human Genetics\r\nUniversity Medical Center Göttingen\r\nGöttingen Germany"],["dc.contributor.affiliation","Altmüller, Janine; 7\r\nCologne Center for Genomics (CCG), Faculty of Medicine and University Hospital Cologne\r\nUniversity of Cologne\r\nCologne Germany"],["dc.contributor.affiliation","Luppe, Johannes; 2\r\nInstitute of Human Genetics\r\nUniversity of Leipzig Medical Center\r\nLeipzig Germany"],["dc.contributor.affiliation","Platzer, Konrad; 2\r\nInstitute of Human Genetics\r\nUniversity of Leipzig Medical Center\r\nLeipzig Germany"],["dc.contributor.affiliation","Dörgeloh, Beate B.; 10\r\nDepartment of Pediatric Hematology and Oncology\r\nHannover Medical School\r\nHannover Germany"],["dc.contributor.affiliation","Busche, Andreas; 11\r\nInstitut für Humangenetik\r\nWestfälische Wilhelms‐Universität Münster\r\nMünster Germany"],["dc.contributor.affiliation","Biskup, Saskia; 12\r\nCeGaT GmbH\r\nCenter for Genomics and Transcriptomics\r\nTübingen Germany"],["dc.contributor.affiliation","Mendes, Marisa I.; 13\r\nLaboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology and Metabolism, Amsterdam Neuroscience\r\nAmsterdam UMC\r\nAmsterdam Netherlands"],["dc.contributor.affiliation","Smith, Desiree E. C.; 13\r\nLaboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology and Metabolism, Amsterdam Neuroscience\r\nAmsterdam UMC\r\nAmsterdam Netherlands"],["dc.contributor.affiliation","Salomons, Gajja S.; 13\r\nLaboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology and Metabolism, Amsterdam Neuroscience\r\nAmsterdam UMC\r\nAmsterdam Netherlands"],["dc.contributor.affiliation","Zibat, Arne; 1\r\nInstitute of Human Genetics\r\nUniversity Medical Center Göttingen\r\nGöttingen Germany"],["dc.contributor.affiliation","Bültmann, Eva; 14\r\nInstitute of Diagnostic and Interventional Neuroradiology\r\nHannover Medical School\r\nHannover Germany"],["dc.contributor.affiliation","Nürnberg, Peter; 7\r\nCologne Center for Genomics (CCG), Faculty of Medicine and University Hospital Cologne\r\nUniversity of Cologne\r\nCologne Germany"],["dc.contributor.affiliation","Spielmann, Malte; 4\r\nInstitut für Humangenetik\r\nUniversitätsklinikum Schleswig‐Holstein\r\nLübeck Germany"],["dc.contributor.affiliation","Lemke, Johannes R.; 2\r\nInstitute of Human Genetics\r\nUniversity of Leipzig Medical Center\r\nLeipzig Germany"],["dc.contributor.affiliation","Li, Yun; 1\r\nInstitute of Human Genetics\r\nUniversity Medical Center Göttingen\r\nGöttingen Germany"],["dc.contributor.affiliation","Zenker, Martin; 16\r\nInstitute of Human Genetics\r\nOtto‐von‐Guericke University Magdeburg\r\nMagdeburg Germany"],["dc.contributor.affiliation","Varshney, Gaurav K.; 3\r\nGenes & Human Disease Research Program\r\nOklahoma Medical Research Foundation\r\nOklahoma City Oklahoma USA"],["dc.contributor.affiliation","Hillen, Hauke S.; 17\r\nResearch Group Structure and Function of Molecular Machines\r\nMax Planck Institute for Multidisciplinary Sciences\r\nGöttingen Germany"],["dc.contributor.affiliation","Kratz, Christian P.; 10\r\nDepartment of Pediatric Hematology and Oncology\r\nHannover Medical School\r\nHannover Germany"],["dc.contributor.author","Bögershausen, Nina"],["dc.contributor.author","Krawczyk, Hannah E."],["dc.contributor.author","Jamra, Rami A."],["dc.contributor.author","Lin, Sheng‐Jia"],["dc.contributor.author","Yigit, Gökhan"],["dc.contributor.author","Hüning, Irina"],["dc.contributor.author","Polo, Anna M."],["dc.contributor.author","Vona, Barbara"],["dc.contributor.author","Huang, Kevin"],["dc.contributor.author","Schmidt, Julia"],["dc.contributor.author","Altmüller, Janine"],["dc.contributor.author","Luppe, Johannes"],["dc.contributor.author","Platzer, Konrad"],["dc.contributor.author","Dörgeloh, Beate B."],["dc.contributor.author","Busche, Andreas"],["dc.contributor.author","Biskup, Saskia"],["dc.contributor.author","Mendes, Marisa I."],["dc.contributor.author","Smith, Desiree E. C."],["dc.contributor.author","Salomons, Gajja S."],["dc.contributor.author","Zibat, Arne"],["dc.contributor.author","Bültmann, Eva"],["dc.contributor.author","Nürnberg, Peter"],["dc.contributor.author","Spielmann, Malte"],["dc.contributor.author","Lemke, Johannes R."],["dc.contributor.author","Li, Yun"],["dc.contributor.author","Zenker, Martin"],["dc.contributor.author","Varshney, Gaurav K."],["dc.contributor.author","Hillen, Hauke S."],["dc.contributor.author","Kratz, Christian P."],["dc.contributor.author","Wollnik, Bernd"],["dc.date.accessioned","2022-11-28T09:45:52Z"],["dc.date.available","2022-11-28T09:45:52Z"],["dc.date.issued","2022-07-21"],["dc.date.updated","2022-11-27T10:11:29Z"],["dc.description.abstract","Based on the identification of novel variants in aminoacyl‐tRNA synthetase (ARS) genes WARS1 and SARS1, the authors define an emerging disease spectrum related to all type 1 ARS genes: aminoacyl‐tRNA synthetase‐related developmental disorders with or without microcephaly (ARS‐DDM).\r\n\r\nimage"],["dc.description.abstract","Aminoacylation of transfer RNA (tRNA) is a key step in protein biosynthesis, carried out by highly specific aminoacyl-tRNA synthetases (ARSs). ARSs have been implicated in autosomal dominant and autosomal recessive human disorders. Autosomal dominant variants in tryptophanyl-tRNA synthetase 1 (WARS1) are known to cause distal hereditary motor neuropathy and Charcot-Marie-Tooth disease, but a recessively inherited phenotype is yet to be clearly defined. Seryl-tRNA synthetase 1 (SARS1) has rarely been implicated in an autosomal recessive developmental disorder. Here, we report five individuals with biallelic missense variants in WARS1 or SARS1, who presented with an overlapping phenotype of microcephaly, developmental delay, intellectual disability, and brain anomalies. Structural mapping showed that the SARS1 variant is located directly within the enzyme's active site, most likely diminishing activity, while the WARS1 variant is located in the N-terminal domain. We further characterize the identified WARS1 variant by showing that it negatively impacts protein abundance and is unable to rescue the phenotype of a CRISPR/Cas9 wars1 knockout zebrafish model. In summary, we describe two overlapping autosomal recessive syndromes caused by variants in WARS1 and SARS1, present functional insights into the pathogenesis of the WARS1-related syndrome and define an emerging disease spectrum: ARS-related developmental disorders with or without microcephaly."],["dc.description.sponsorship","Deutsches Zentrum für Herz‐Kreislaufforschung http://dx.doi.org/10.13039/100010447"],["dc.description.sponsorship","Deutsche Forschungsgemeinschaft http://dx.doi.org/10.13039/501100001659"],["dc.description.sponsorship","Presbyterian Health Foundation http://dx.doi.org/10.13039/100001298"],["dc.description.sponsorship","University Medical Center Göttingen"],["dc.description.sponsorship","Oklahoma Medical Research Foundation http://dx.doi.org/10.13039/100008907"],["dc.identifier.doi","10.1002/humu.24430"],["dc.identifier.pmid","35790048"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/117321"],["dc.identifier.url","https://mbexc.uni-goettingen.de/literature/publications/517"],["dc.identifier.url","https://sfb1190.med.uni-goettingen.de/production/literature/publications/180"],["dc.identifier.url","https://for2848.gwdguser.de/literature/publications/34"],["dc.language.iso","en"],["dc.relation","EXC 2067: Multiscale Bioimaging"],["dc.relation","SFB 1190: Transportmaschinen und Kontaktstellen zellulärer Kompartimente"],["dc.relation","FOR 2848: Architektur und Heterogenität der inneren mitochondrialen Membran auf der Nanoskala"],["dc.relation","FOR 2848 | St01: Structure and distribution of ribosomes at the inner mitochondrial membrane"],["dc.relation.eissn","1098-1004"],["dc.relation.issn","1059-7794"],["dc.relation.workinggroup","RG Wollnik"],["dc.relation.workinggroup","RG Hillen (Structure and Function of Molecular Machines)"],["dc.rights","CC BY-NC-ND 4.0"],["dc.title","WARS1 and SARS1: Two tRNA synthetases implicated in autosomal recessive microcephaly"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","1082"],["dc.bibliographiccitation.issue","5"],["dc.bibliographiccitation.journal","Cell"],["dc.bibliographiccitation.lastpage","1093"],["dc.bibliographiccitation.volume","171"],["dc.contributor.author","Hillen, Hauke S."],["dc.contributor.author","Parshin, Andrey V."],["dc.contributor.author","Agaronyan, Karen"],["dc.contributor.author","Morozov, Yaroslav I."],["dc.contributor.author","Graber, James J."],["dc.contributor.author","Chernev, Aleksandar"],["dc.contributor.author","Schwinghammer, Kathrin"],["dc.contributor.author","Urlaub, Henning"],["dc.contributor.author","Anikin, Michael"],["dc.contributor.author","Cramer, Patrick"],["dc.contributor.author","Temiakov, Dmitry"],["dc.date.accessioned","2018-01-09T12:26:24Z"],["dc.date.available","2018-01-09T12:26:24Z"],["dc.date.issued","2017"],["dc.description.abstract","In human mitochondria, transcription termination events at a G-quadruplex region near the replication origin are thought to drive replication of mtDNA by generation of an RNA primer. This process is suppressed by a key regulator of mtDNA-the transcription factor TEFM. We determined the structure of an anti-termination complex in which TEFM is bound to transcribing mtRNAP. The structure reveals interactions of the dimeric pseudonuclease core of TEFM with mobile structural elements in mtRNAP and the nucleic acid components of the elongation complex (EC). Binding of TEFM to the DNA forms a downstream \"sliding clamp,\" providing high processivity to the EC. TEFM also binds near the RNA exit channel to prevent formation of the RNA G-quadruplex structure required for termination and thus synthesis of the replication primer. Our data provide insights into target specificity of TEFM and mechanisms by which it regulates the switch between transcription and replication of mtDNA."],["dc.identifier.doi","10.1016/j.cell.2017.09.035"],["dc.identifier.pmid","29033127"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/11586"],["dc.language.iso","en"],["dc.notes.status","final"],["dc.relation.eissn","1097-4172"],["dc.title","Mechanism of Transcription Anti-termination in Human Mitochondria"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","e41"],["dc.bibliographiccitation.issue","a2"],["dc.bibliographiccitation.journal","Acta Crystallographica Section A Foundations and Advances"],["dc.bibliographiccitation.lastpage","e42"],["dc.bibliographiccitation.volume","74"],["dc.contributor.author","Hillen, Hauke"],["dc.date.accessioned","2022-03-01T11:47:06Z"],["dc.date.available","2022-03-01T11:47:06Z"],["dc.date.issued","2018"],["dc.identifier.doi","10.1107/S2053273318094585"],["dc.identifier.pii","S2053273318094585"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/103913"],["dc.notes.intern","DOI-Import GROB-531"],["dc.relation.issn","2053-2733"],["dc.rights.uri","http://journals.iucr.org/services/copyrightpolicy.html"],["dc.title","Structural basis of human mitochondrial transcription"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","82"],["dc.bibliographiccitation.journal","Current Opinion in Virology"],["dc.bibliographiccitation.lastpage","90"],["dc.bibliographiccitation.volume","48"],["dc.contributor.author","Hillen, Hauke S."],["dc.date.accessioned","2021-06-01T10:49:31Z"],["dc.date.available","2021-06-01T10:49:31Z"],["dc.date.issued","2021"],["dc.description.abstract","Coronaviruses use an RNA-dependent RNA polymerase (RdRp) to replicate and express their genome. The RdRp associates with additional non-structural proteins (nsps) to form a replication–transcription complex (RTC) that carries out RNA synthesis, capping and proofreading. However, the structure of the RdRp long remained elusive, thus limiting our understanding of coronavirus genome expression and replication. Recently, the cryo-electron microscopy structure of SARS-CoV-1 RdRp was reported. Driven by the ongoing COVID-19 pandemic, structural data on the SARS-CoV-2 polymerase and associated factors has since emerged at an unprecedented pace, with more than twenty structures released to date. This review provides an overview of the currently available coronavirus RdRp structures and outlines how they have, together with functional studies, led to a molecular understanding of the viral polymerase, its interactions with accessory factors and the mechanisms by which promising antivirals may inhibit coronavirus replication."],["dc.identifier.doi","10.1016/j.coviro.2021.03.010"],["dc.identifier.pmid","33945951"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/86321"],["dc.identifier.url","https://mbexc.uni-goettingen.de/literature/publications/247"],["dc.identifier.url","https://sfb1190.med.uni-goettingen.de/production/literature/publications/142"],["dc.identifier.url","https://for2848.gwdguser.de/literature/publications/15"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-425"],["dc.relation","EXC 2067: Multiscale Bioimaging"],["dc.relation","SFB 1190: Transportmaschinen und Kontaktstellen zellulärer Kompartimente"],["dc.relation","FOR 2848: Architektur und Heterogenität der inneren mitochondrialen Membran auf der Nanoskala"],["dc.relation","FOR 2848 | St01: Structure and distribution of ribosomes at the inner mitochondrial membrane"],["dc.relation.issn","1879-6257"],["dc.relation.workinggroup","RG Hillen (Structure and Function of Molecular Machines)"],["dc.rights","CC BY 4.0"],["dc.title","Structure and function of SARS-CoV-2 polymerase"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","overview_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","712-716"],["dc.bibliographiccitation.issue","7839"],["dc.bibliographiccitation.journal","Nature"],["dc.bibliographiccitation.lastpage","716"],["dc.bibliographiccitation.volume","588"],["dc.contributor.author","Bonekamp, Nina A."],["dc.contributor.author","Peter, Bradley"],["dc.contributor.author","Hillen, Hauke S."],["dc.contributor.author","Felser, Andrea"],["dc.contributor.author","Bergbrede, Tim"],["dc.contributor.author","Choidas, Axel"],["dc.contributor.author","Horn, Moritz"],["dc.contributor.author","Unger, Anke"],["dc.contributor.author","Di Lucrezia, Raffaella"],["dc.contributor.author","Atanassov, Ilian"],["dc.contributor.author","Li, Xinping"],["dc.contributor.author","Koch, Uwe"],["dc.contributor.author","Menninger, Sascha"],["dc.contributor.author","Boros, Joanna"],["dc.contributor.author","Habenberger, Peter"],["dc.contributor.author","Giavalisco, Patrick"],["dc.contributor.author","Cramer, Patrick"],["dc.contributor.author","Denzel, Martin S."],["dc.contributor.author","Nussbaumer, Peter"],["dc.contributor.author","Klebl, Bert"],["dc.contributor.author","Falkenberg, Maria"],["dc.contributor.author","Gustafsson, Claes M."],["dc.contributor.author","Larsson, Nils-Göran"],["dc.date.accessioned","2022-02-21T14:38:53Z"],["dc.date.available","2022-02-21T14:38:53Z"],["dc.date.issued","2020"],["dc.description.abstract","Altered expression of mitochondrial DNA (mtDNA) occurs in ageing and a range of human pathologies (for example, inborn errors of metabolism, neurodegeneration and cancer). Here we describe first-in-class specific inhibitors of mitochondrial transcription (IMTs) that target the human mitochondrial RNA polymerase (POLRMT), which is essential for biogenesis of the oxidative phosphorylation (OXPHOS) system1-6. The IMTs efficiently impair mtDNA transcription in a reconstituted recombinant system and cause a dose-dependent inhibition of mtDNA expression and OXPHOS in cell lines. To verify the cellular target, we performed exome sequencing of mutagenized cells and identified a cluster of amino acid substitutions in POLRMT that cause resistance to IMTs. We obtained a cryo-electron microscopy (cryo-EM) structure of POLRMT bound to an IMT, which further defined the allosteric binding site near the active centre cleft of POLRMT. The growth of cancer cells and the persistence of therapy-resistant cancer stem cells has previously been reported to depend on OXPHOS7-17, and we therefore investigated whether IMTs have anti-tumour effects. Four weeks of oral treatment with an IMT is well-tolerated in mice and does not cause OXPHOS dysfunction or toxicity in normal tissues, despite inducing a strong anti-tumour response in xenografts of human cancer cells. In summary, IMTs provide a potent and specific chemical biology tool to study the role of mtDNA expression in physiology and disease."],["dc.identifier.doi","10.1038/s41586-020-03048-z"],["dc.identifier.pmid","33328633"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/100151"],["dc.identifier.url","https://mbexc.uni-goettingen.de/literature/publications/105"],["dc.identifier.url","https://for2848.gwdguser.de/literature/publications/19"],["dc.language.iso","en"],["dc.relation","EXC 2067: Multiscale Bioimaging"],["dc.relation","FOR 2848: Architektur und Heterogenität der inneren mitochondrialen Membran auf der Nanoskala"],["dc.relation","FOR 2848 | St01: Structure and distribution of ribosomes at the inner mitochondrial membrane"],["dc.relation.eissn","1476-4687"],["dc.relation.issn","0028-0836"],["dc.relation.workinggroup","RG Cramer"],["dc.relation.workinggroup","RG Hillen (Structure and Function of Molecular Machines)"],["dc.title","Small-molecule inhibitors of human mitochondrial DNA transcription"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","3672"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Nature Communications"],["dc.bibliographiccitation.volume","12"],["dc.contributor.author","Hillen, Hauke S."],["dc.contributor.author","Lavdovskaia, Elena"],["dc.contributor.author","Nadler, Franziska"],["dc.contributor.author","Hanitsch, Elisa"],["dc.contributor.author","Linden, Andreas"],["dc.contributor.author","Bohnsack, Katherine E."],["dc.contributor.author","Urlaub, Henning"],["dc.contributor.author","Richter-Dennerlein, Ricarda"],["dc.date.accessioned","2021-07-05T15:00:30Z"],["dc.date.available","2021-07-05T15:00:30Z"],["dc.date.issued","2021"],["dc.description.abstract","Abstract Ribosome biogenesis requires auxiliary factors to promote folding and assembly of ribosomal proteins and RNA. Particularly, maturation of the peptidyl transferase center (PTC) is mediated by conserved GTPases, but the molecular basis is poorly understood. Here, we define the mechanism of GTPase-driven maturation of the human mitochondrial large ribosomal subunit (mtLSU) using endogenous complex purification, in vitro reconstitution and cryo-EM. Structures of transient native mtLSU assembly intermediates that accumulate in GTPBP6-deficient cells reveal how the biogenesis factors GTPBP5, MTERF4 and NSUN4 facilitate PTC folding. Addition of recombinant GTPBP6 reconstitutes late mtLSU biogenesis in vitro and shows that GTPBP6 triggers a molecular switch and progression to a near-mature PTC state. Additionally, cryo-EM analysis of GTPBP6-treated mature mitochondrial ribosomes reveals the structural basis for the dual-role of GTPBP6 in ribosome biogenesis and recycling. Together, these results provide a framework for understanding step-wise PTC folding as a critical conserved quality control checkpoint."],["dc.description.sponsorship","Open-Access-Finanzierung durch die Universitätsmedizin Göttingen 2021"],["dc.identifier.doi","10.1038/s41467-021-23702-y"],["dc.identifier.pii","23702"],["dc.identifier.pmid","34135319"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/87838"],["dc.identifier.url","https://mbexc.uni-goettingen.de/literature/publications/316"],["dc.language.iso","en"],["dc.notes.intern","DOI Import DOI-Import GROB-441"],["dc.relation","EXC 2067: Multiscale Bioimaging"],["dc.relation.eissn","2041-1723"],["dc.relation.workinggroup","RG Hillen (Structure and Function of Molecular Machines)"],["dc.relation.workinggroup","RG Richter-Dennerlein (Mitoribosome Assembly)"],["dc.rights","CC BY 4.0"],["dc.title","Structural basis of GTPase-mediated mitochondrial ribosome biogenesis and recycling"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.contributor.author","Hillen, Hauke S."],["dc.contributor.author","Lavdovskaia, Elena"],["dc.contributor.author","Nadler, Franziska"],["dc.contributor.author","Hanitsch, Elisa"],["dc.contributor.author","Linden, Andreas"],["dc.contributor.author","Bohnsack, Katherine E."],["dc.contributor.author","Urlaub, Henning"],["dc.contributor.author","Richter-Dennerlein, Ricarda"],["dc.date.accessioned","2022-02-23T16:35:33Z"],["dc.date.available","2022-02-23T16:35:33Z"],["dc.date.issued","2021"],["dc.identifier.doi","10.1101/2021.03.17.435767"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/100377"],["dc.identifier.url","https://mbexc.uni-goettingen.de/literature/publications/241"],["dc.relation","EXC 2067: Multiscale Bioimaging"],["dc.relation.workinggroup","RG Hillen (Structure and Function of Molecular Machines)"],["dc.relation.workinggroup","RG Richter-Dennerlein (Mitoribosome Assembly)"],["dc.title","Structural basis of GTPase-mediated mitochondrial ribosome biogenesis and recycling"],["dc.type","preprint"],["dc.type.internalPublication","unknown"],["dspace.entity.type","Publication"]]