11 results on '"Lambacher, Nils J."'
Search Results
2. Caenorhabditis elegans telomere-binding proteins TEBP-1 and TEBP-2 adapt the Myb module to dimerize and bind telomeric DNA.
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Padmanaban, Shilpa, Lambacher, Nils J., Tesmer, Valerie M., Jingjing Zhang, Hiroki Shibuya, and Nandakumar, Jayakrishnan
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CAENORHABDITIS elegans , *DNA repair , *ANIMAL clutches , *DNA , *PROTEINS , *MODULAR design - Abstract
Protecting chromosome ends from misrecognition as double-stranded (ds) DNA breaks is fundamental to eukaryotic viability. The protein complex shelterin prevents a DNA damage response at mammalian telomeres. Mammalian shelterin proteins TRF1 and TRF2 and their homologs in yeast and protozoa protect telomeric dsDNA. N-terminal homodimerization and C-terminal Myb-domain-mediated dsDNA binding are two structural hallmarks of end protection by TRF homologs. Yet our understanding of how Caenorhabditis elegans protects its telomeric dsDNA is limited. Recently identified C. elegans proteins TEBP-1 (also called DTN-1) and TEBP-2 (also called DTN-2) are functional homologs of TRF proteins, but how they bind DNA and whether or how they dimerize is not known. TEBP-1 and TEBP-2 harbor three Myb-containing domains (MCDs) and no obvious dimerization domain. We demonstrate biochemically that only the third MCD binds DNA. We solve the X-ray crystal structure of TEBP-2 MCD3 with telomeric dsDNA to reveal the structural mechanism of telomeric dsDNA protection in C. elegans. Mutagenesis of the DNA-binding site of TEBP-1 and TEBP-2 compromises DNA binding in vitro, and increases DNA damage signaling, lengthens telomeres, and decreases brood size in vivo. Via an X-ray crystal structure, biochemical validation of the dimerization interface, and SEC-MALS analysis, we demonstrate that MCD1 and MCD2 form a composite dimerization module that facilitates not only TEBP-1 and TEBP-2 homodimerization but also heterodimerization. These findings provide fundamental insights into C. elegans telomeric dsDNA protection and highlight how different eukaryotes have evolved distinct strategies to solve the chromosome end protection problem. [ABSTRACT FROM AUTHOR]
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- 2024
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3. CiliaCarta: An integrated and validated compendium of ciliary genes
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van Dam, Teunis J. P., primary, Kennedy, Julie, additional, van der Lee, Robin, additional, de Vrieze, Erik, additional, Wunderlich, Kirsten A., additional, Rix, Suzanne, additional, Dougherty, Gerard W., additional, Lambacher, Nils J., additional, Li, Chunmei, additional, Jensen, Victor L., additional, Leroux, Michel R., additional, Hjeij, Rim, additional, Horn, Nicola, additional, Texier, Yves, additional, Wissinger, Yasmin, additional, van Reeuwijk, Jeroen, additional, Wheway, Gabrielle, additional, Knapp, Barbara, additional, Scheel, Jan F., additional, Franco, Brunella, additional, Mans, Dorus A., additional, van Wijk, Erwin, additional, Képès, François, additional, Slaats, Gisela G., additional, Toedt, Grischa, additional, Kremer, Hannie, additional, Omran, Heymut, additional, Szymanska, Katarzyna, additional, Koutroumpas, Konstantinos, additional, Ueffing, Marius, additional, Nguyen, Thanh-Minh T., additional, Letteboer, Stef J. F., additional, Oud, Machteld M., additional, van Beersum, Sylvia E. C., additional, Schmidts, Miriam, additional, Beales, Philip L., additional, Lu, Qianhao, additional, Giles, Rachel H., additional, Szklarczyk, Radek, additional, Russell, Robert B., additional, Gibson, Toby J., additional, Johnson, Colin A., additional, Blacque, Oliver E., additional, Wolfrum, Uwe, additional, Boldt, Karsten, additional, Roepman, Ronald, additional, Hernandez-Hernandez, Victor, additional, and Huynen, Martijn A., additional
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- 2019
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4. Role for intraflagellar transport in building a functional transition zone
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Jensen, Victor L, primary, Lambacher, Nils J, additional, Li, Chunmei, additional, Mohan, Swetha, additional, Williams, Corey L, additional, Inglis, Peter N, additional, Yoder, Bradley K, additional, Blacque, Oliver E, additional, and Leroux, Michel R, additional
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- 2018
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5. Primary Cilium Formation and Ciliary Protein Trafficking Is Regulated by the Atypical MAP Kinase MAPK15 in Caenorhabditis elegans and Human Cells
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Kazatskaya, Anna, primary, Kuhns, Stefanie, additional, Lambacher, Nils J, additional, Kennedy, Julie E, additional, Brear, Andrea G, additional, McManus, Gavin J, additional, Sengupta, Piali, additional, and Blacque, Oliver E, additional
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- 2017
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6. KIAA0556 is a novel ciliary basal body component mutated in Joubert syndrome
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Sanders, Anna A. W. M., de Vrieze, Erik, Alazami, Anas M., Alzahrani, Fatema, Malarkey, Erik B., Sorusch, Nasrin, Tebbe, Lars, Kuhns, Stefanie, van Dam, Teunis J. P., Alhashem, Amal, Tabarki, Brahim, Lu, Qianhao, Lambacher, Nils J., Kennedy, Julie E., Bowie, Rachel V., Hetterschijt, Lisette, van Beersum, Sylvia, van Reeuwijk, Jeroen, Boldt, Karsten, Kremer, Hannie, Kesterson, Robert A., Monies, Dorota, Abouelhoda, Mohamed, Roepman, Ronald, Huynen, Martijn H., Ueffing, Marius, Russell, Rob B., Wolfrum, Uwe, Yoder, Bradley K., van Wijk, Erwin, Alkuraya, Fowzan S., and Blacque, Oliver E.
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Adult ,Male ,K04F10.2 ,KIAA0556 ,Microtubule ,Microtubules ,Retina ,Mice ,Joubert syndrome ,Cerebellum ,Animals ,Humans ,Abnormalities, Multiple ,Exome ,Cilia ,Eye Abnormalities ,Sensory disorders Radboud Institute for Molecular Life Sciences [Radboudumc 12] ,Caenorhabditis elegans ,Child ,Cells, Cultured ,Adenosine Triphosphatases ,ADP-Ribosylation Factors ,Research ,Brain ,Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6] ,Kidney Diseases, Cystic ,Basal Bodies ,Pedigree ,Mice, Inbred C57BL ,Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11] ,Basal body ,Child, Preschool ,Mutation ,Female ,Katanin ,Microtubule-Associated Proteins ,Protein Binding - Abstract
Background Joubert syndrome (JBTS) and related disorders are defined by cerebellar malformation (molar tooth sign), together with neurological symptoms of variable expressivity. The ciliary basis of Joubert syndrome related disorders frequently extends the phenotype to tissues such as the eye, kidney, skeleton and craniofacial structures. Results Using autozygome and exome analyses, we identified a null mutation in KIAA0556 in a multiplex consanguineous family with hallmark features of mild Joubert syndrome. Patient-derived fibroblasts displayed reduced ciliogenesis potential and abnormally elongated cilia. Investigation of disease pathophysiology revealed that Kiaa0556-/- null mice possess a Joubert syndrome-associated brain-restricted phenotype. Functional studies in Caenorhabditis elegans nematodes and cultured human cells support a conserved ciliary role for KIAA0556 linked to microtubule regulation. First, nematode KIAA0556 is expressed almost exclusively in ciliated cells, and the worm and human KIAA0556 proteins are enriched at the ciliary base. Second, C. elegans KIAA0056 regulates ciliary A-tubule number and genetically interacts with an ARL13B (JBTS8) orthologue to control cilium integrity. Third, human KIAA0556 binds to microtubules in vitro and appears to stabilise microtubule networks when overexpressed. Finally, human KIAA0556 biochemically interacts with ciliary proteins and p60/p80 katanins. The latter form a microtubule-severing enzyme complex that regulates microtubule dynamics as well as ciliary functions. Conclusions We have identified KIAA0556 as a novel microtubule-associated ciliary base protein mutated in Joubert syndrome. Consistent with the mild patient phenotype, our nematode, mice and human cell data support the notion that KIAA0556 has a relatively subtle and variable cilia-related function, which we propose is related to microtubule regulation. Electronic supplementary material The online version of this article (doi:10.1186/s13059-015-0858-z) contains supplementary material, which is available to authorized users.
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- 2015
7. CiliaCarta: an integrated and validated compendium of ciliary genes
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van Dam, Teunis J. P., primary, Kennedy, Julie, additional, Lee, Robin van der, additional, Vrieze, Erik de, additional, Wunderlich, Kirsten A., additional, Rix, Suzanne, additional, Dougherty, Gerard W., additional, Lambacher, Nils J., additional, Li, Chunmei, additional, Jensen, Victor L., additional, Leroux, Michel R., additional, Hjeij, Rim, additional, Horn, Nicola, additional, Texier, Yves, additional, Wissinger, Yasmin, additional, van Reeuwijk, Jeroen, additional, Wheway, Gabrielle, additional, Knapp, Barbara, additional, Scheel, Jan F., additional, Franco, Brunella, additional, Mans, Dorus A., additional, van Wijk, Erwin, additional, Képès, François, additional, Slaats, Gisela G., additional, Toedt, Grischa, additional, Kremer, Hannie, additional, Omran, Heymut, additional, Szymanska, Katarzyna, additional, Koutroumpas, Konstantinos, additional, Ueffing, Marius, additional, Nguyen, Thanh-Minh T., additional, Letteboer, Stef J.F., additional, Oud, Machteld M., additional, van Beersum, Sylvia E. C., additional, Schmidts, Miriam, additional, Beales, Philip L., additional, Lu, Qianhao, additional, Giles, Rachel H., additional, Szklarczyk, Radek, additional, Russell, Robert B., additional, Gibson, Toby J., additional, Johnson, Colin A., additional, Blacque, Oliver E., additional, Wolfrum, Uwe, additional, Boldt, Karsten, additional, Roepman, Ronald, additional, Hernandez-Hernandez, Victor, additional, and Huynen, Martijn A., additional
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- 2017
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8. TMEM107 recruits ciliopathy proteins to subdomains of the ciliary transition zone and causes Joubert syndrome
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Lambacher, Nils J., primary, Bruel, Ange-Line, additional, van Dam, Teunis J. P., additional, Szymańska, Katarzyna, additional, Slaats, Gisela G., additional, Kuhns, Stefanie, additional, McManus, Gavin J., additional, Kennedy, Julie E., additional, Gaff, Karl, additional, Wu, Ka Man, additional, van der Lee, Robin, additional, Burglen, Lydie, additional, Doummar, Diane, additional, Rivière, Jean-Baptiste, additional, Faivre, Laurence, additional, Attié-Bitach, Tania, additional, Saunier, Sophie, additional, Curd, Alistair, additional, Peckham, Michelle, additional, Giles, Rachel H., additional, Johnson, Colin A., additional, Huynen, Martijn A., additional, Thauvin-Robinet, Christel, additional, and Blacque, Oliver E., additional
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- 2015
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9. Primary Cilium Formation and Ciliary Protein Trafficking Is Regulated by the Atypical MAP Kinase MAPK15 in Caenorhabditis elegansand Human Cells
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Kazatskaya, Anna, Kuhns, Stefanie, Lambacher, Nils J, Kennedy, Julie E, Brear, Andrea G, McManus, Gavin J, Sengupta, Piali, and Blacque, Oliver E
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Kazatskaya et al.uncover a role for the atypical MAP kinase MAPK15 in regulating primary cilium structure and morphology in both C. elegansand human..Motile and immotile (or primary) cilia are microtubule-based structures that mediate multiple cellular functions, including the transduction of environmental cues, developmental signaling, cellular motility, and modulation of fluid flow. Although their core architectures are similar, motile and primary cilia exhibit marked structural differences that underlie distinct functional properties. However, the extent to which ciliogenesis mechanisms are shared between these different cilia types is not fully described. Here, we report that the atypical MAP kinase MAPK15 (ERK7/8), implicated in the formation of vertebrate motile cilia, also regulates the formation of primary cilia in Caenorhabditis eleganssensory neurons and human cells. We find that MAPK15 localizes to a basal body subdomain with the ciliopathy protein BBS7 and to cell–cell junctions. MAPK15 also regulates the localization of ciliary proteins involved in cilium structure, transport, and signaling. Our results describe a primary cilia-related role for this poorly studied member of the MAPK family in vivo, and indicate a broad requirement for MAPK15 in the formation of multiple ciliary classes across species.
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- 2017
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10. TMEM107 recruits ciliopathy proteins to subdomains of the ciliary transition zone and causes Joubert syndrome
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Lambacher, Nils J., Bruel, Ange-Line, van Dam, Teunis J. P., Szymańska, Katarzyna, Slaats, Gisela G., Kuhns, Stefanie, McManus, Gavin J., Kennedy, Julie E., Gaff, Karl, Wu, Ka Man, van der Lee, Robin, Burglen, Lydie, Doummar, Diane, Rivière, Jean-Baptiste, Faivre, Laurence, Attié-Bitach, Tania, Saunier, Sophie, Curd, Alistair, Peckham, Michelle, Giles, Rachel H., Johnson, Colin A., Huynen, Martijn A., Thauvin-Robinet, Christel, and Blacque, Oliver E.
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The transition zone (TZ) ciliary subcompartment is thought to control cilium composition and signalling by facilitating a protein diffusion barrier at the ciliary base. TZ defects cause ciliopathies such as Meckel–Gruber syndrome (MKS), nephronophthisis (NPHP) and Joubert syndrome (JBTS). However, the molecular composition and mechanisms underpinning TZ organization and barrier regulation are poorly understood. To uncover candidate TZ genes, we employed bioinformatics (coexpression and co-evolution) and identified TMEM107 as a TZ protein mutated in oral–facial–digital syndrome and JBTS patients. Mechanistic studies in Caenorhabditis elegans showed that TMEM-107 controls ciliary composition and functions redundantly with NPHP-4 to regulate cilium integrity, TZ docking and assembly of membrane to microtubule Y-link connectors. Furthermore, nematode TMEM-107 occupies an intermediate layer of the TZ-localized MKS module by organizing recruitment of the ciliopathy proteins MKS-1, TMEM-231 (JBTS20) and JBTS-14 (TMEM237). Finally, MKS module membrane proteins are immobile and super-resolution microscopy in worms and mammalian cells reveals periodic localizations within the TZ. This work expands the MKS module of ciliopathy-causing TZ proteins associated with diffusion barrier formation and provides insight into TZ subdomain architecture.
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- 2016
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11. CiliaCarta: An integrated and validated compendium of ciliary genes
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Gerard W. Dougherty, Victor L. Jensen, Jan Frederik Scheel, Katarzyna Szymanska, Uwe Wolfrum, Radek Szklarczyk, Miriam Schmidts, Julie Kennedy, Erwin van Wijk, Brunella Franco, Toby J. Gibson, Machteld M. Oud, Chunmei Li, Nils J. Lambacher, Erik de Vrieze, Grischa Toedt, Teunis J. P. van Dam, Karsten Boldt, Heymut Omran, Yves Texier, Rachel H. Giles, Ronald Roepman, Kirsten A. Wunderlich, Sylvia E. C. van Beersum, Oliver E. Blacque, Thanh-Minh T. Nguyen, Konstantinos Koutroumpas, Hannie Kremer, Nicola Horn, Martijn A. Huynen, Michel R. Leroux, Gabrielle Wheway, Rim Hjeij, Philip L. Beales, Gisela G. Slaats, Robert B. Russell, Robin van der Lee, François Képès, Yasmin Wissinger, Barbara Knapp, Dorus A. Mans, Suzanne Rix, Marius Ueffing, Colin A. Johnson, Stef J.F. Letteboer, Victor Hernandez-Hernandez, Qianhao Lu, Jeroen van Reeuwijk, Sub Bioinformatics, Theoretical Biology and Bioinformatics, MUMC+: DA KG Lab Centraal Lab (9), Klinische Genetica, RS: GROW - R4 - Reproductive and Perinatal Medicine, van Dam, Teunis J P, Kennedy, Julie, van der Lee, Robin, de Vrieze, Erik, Wunderlich, Kirsten A, Rix, Suzanne, Dougherty, Gerard W, Lambacher, Nils J, Li, Chunmei, Jensen, Victor L, Leroux, Michel R, Hjeij, Rim, Horn, Nicola, Texier, Yve, Wissinger, Yasmin, van Reeuwijk, Jeroen, Wheway, Gabrielle, Knapp, Barbara, Scheel, Jan F, Franco, Brunella, Mans, Dorus A, van Wijk, Erwin, Képès, Françoi, Slaats, Gisela G, Toedt, Grischa, Kremer, Hannie, Omran, Heymut, Szymanska, Katarzyna, Koutroumpas, Konstantino, Ueffing, Mariu, Nguyen, Thanh-Minh T, Letteboer, Stef J F, Oud, Machteld M, van Beersum, Sylvia E C, Schmidts, Miriam, Beales, Philip L, Lu, Qianhao, Giles, Rachel H, Szklarczyk, Radek, Russell, Robert B, Gibson, Toby J, Johnson, Colin A, Blacque, Oliver E, Wolfrum, Uwe, Boldt, Karsten, Roepman, Ronald, Hernandez-Hernandez, Victor, and Huynen, Martijn A
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Proteomics ,Sensory Receptors ,Nematoda ,Social Sciences ,Ciliopathies ,Biochemistry ,Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12] ,Transcriptome ,0302 clinical medicine ,Animal Cells ,Psychology ,RETINAL PHOTORECEPTOR CELLS ,Exome ,Neurons ,0303 health sciences ,030302 biochemistry & molecular biology ,Eukaryota ,Genomics ,PRIMARY CILIUM ,thecilium ,3. Good health ,Nucleic acids ,Genetic interference ,Osteichthyes ,Medicine ,Epigenetics ,Cellular Structures and Organelles ,Cellular Types ,proteomic databases ,Sensory Receptor Cells ,Science ,education ,Ciliary genes ,LEBER CONGENITAL AMAUROSIS ,03 medical and health sciences ,Genetics ,Cilia ,Caenorhabditis elegans ,IDENTIFICATION ,MUTATIONS ,Embryos ,cilia ,Organisms ,Biology and Life Sciences ,Bayes Theorem ,Molecular Sequence Annotation ,medicine.disease ,Invertebrates ,Fish ,ciliary proteome ,Animal Studies ,Caenorhabditis ,Gene expression ,embryos ,030217 neurology & neurosurgery ,Developmental Biology ,Neuroscience ,Photoreceptors ,Candidate gene ,Embryology ,Oligonucleotides ,Morpholino ,Database and Informatics Methods ,RNA interference ,Bayesian classifier ,TRANSITION ZONE ,Zebrafish ,Antisense Oligonucleotides ,Multidisciplinary ,Spectrometric Identification of Proteins ,Proteomic Databases ,Nucleotides ,Cilium ,Stable Isotope Labeling by Amino Acids in Cell Culture ,photoreceptors ,Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6] ,Animal Models ,Phenotype ,INTRAFLAGELLAR TRANSPORT ,DIFFERENTIATION ,Experimental Organism Systems ,Caenorhabditis Elegans ,Vertebrates ,Sensory Perception ,Research Article ,Signal Transduction ,EXPRESSION ,Stable isotope labeling by amino acids in cell culture ,Computational biology ,Biology ,Research and Analysis Methods ,SOLUTE-CARRIER-PROTEIN ,Model Organisms ,medicine ,Animals ,data integration ,030304 developmental biology ,Afferent Neurons ,Reproducibility of Results ,Cell Biology ,zebrafish ,biology.organism_classification ,Ciliopathy ,Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11] ,Biological Databases ,Cellular Neuroscience ,RNA ,OSCP1 ,CiliaCarta - Abstract
The cilium is an essential organelle at the surface of mammalian cells whose dysfunction causes a wide range of genetic diseases collectively called ciliopathies. The current rate at which new ciliopathy genes are identified suggests that many ciliary components remain undiscovered. We generated and rigorously analyzed genomic, proteomic, transcriptomic and evolutionary data and systematically integrated these using Bayesian statistics into a predictive score for ciliary function. This resulted in 285 candidate ciliary genes. We generated independent experimental evidence of ciliary associations for 24 out of 36 analyzed candidate proteins using multiple cell and animal model systems (mouse, zebrafish and nematode) and techniques. For example, we show that OSCP1, which has previously been implicated in two distinct non-ciliary processes, causes ciliogenic and ciliopathy-associated tissue phenotypes when depleted in zebrafish. The candidate list forms the basis of CiliaCarta, a comprehensive ciliary compendium covering 956 genes. The resource can be used to objectively prioritize candidate genes in whole exome or genome sequencing of ciliopathy patients and can be accessed at http://bioinformatics.bio.uu.nl/john/syscilia/ciliacarta/. This work was supported by the European Community’s Seventh Framework Programme [241955, 278568 to MU and KB, 602273 to RS]; the Virgo consortium, funded by the Dutch government [FES0908 to TvD, RvdL and MAH]; the Netherlands Genomics Initiative [050-060-452 to TvD, RvdL and MAH]; the Canadian Institutes of Health Research [MOP-142243, MOP-82870 and PJT-156042 to MRL]; Michael Smith Foundation for Health Research to MRL and VLJ; Kidney Research Scientist Core Education and National Training fellowship to VLJ; The Foundation Fighting Blindness [PPA-0717-0719-RAD to UW, RR, and MU]; the Dutch Kidney Foundation “KOUNCIL” consortium [CP11.18 to RHG, PLB and RR]; The Deutsche Forschungsgemeinschaft [Excellence grant CellNetworks to RBR and QL, CRC1140 “Kidney Disease – From Genes to Mechanisms” to MS, collaborative research center grant SFB-1411 KIDGEM to MS]; Metakids Foundation to RS; the National Institute for Health Research to PLB and VH-H. PLB is an NIHR Senior Investigator; Radboudumc Hypatia Tenure Track Fellowship, Radboud Universiteit excellence fellowship, ERC starting grant TREATCilia, grant agreement no. 716344 to MS; and the Netherlands Organization for Scientific Research [NWO Vici-865.12.005 to RR].
- Published
- 2019
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