Prof. Dr. Beat Suter
We are fascinated by the way animals regulate cellular differentiation and proliferation during development. We are addressing these questions in the invertebrate model system Drosophila because of its incredibly powerful genetic tools that allow us to experimentally explore functional aspects of cellular regulation in meaningful ways. We are trying to find out how localization of mRNAs and organelles to specific regions of the cell controls development. In the second research focus we try to figure out how cellular physiology talks to the cell cycle regulatory network to control division of cells.
Cell cycle related projects
Controlling development by localizing mRNAs and organelles
A large proportion of mRNAs, proteins and organelles needs to become localized to specific and divers cellular compartments in order to polarize cells, to direct cellular development, and to efficiently focus the expression of proteins to specific regions of cells. Targeted delivery of mRNAs also provides complex cells with the opportunity to rapidly, locally and temporally control gene expression through local induction of translation, for instance through a local signal. Surprisingly, a very small number of cellular transport systems are responsible for generating a larger number of diverse localization patterns. Particularly transport towards the minus ends of microtubules depends almost exclusively on the cytoplasmic dynein motor. Coupling different cargo adaptors and using different gears and a clutch provides solutions for the required activities. We study aspects of the dynein / dynactin / BicD-mediated localization process to learn more about how this molecular motor localizes his amazing variety of cargos.
Aside from the basic science aspect there is also a human disease aspects to this research. Components of this localization machinery have been linked to human diseases. Lis1 (Lissencephaly-1) plays a crucial role in brain development and mutations in the human BICD2 gene cause Spinal Muscular Atrophy and also defects in brain development. The Drosophila model allows us to study these genes utilizing a variety of experimental approaches.
Selected primary research articles:
Vazquez-Pianzola et al., RNA Biology, doi: 10.1080/15476286.2016.1251542.
Vazquez-Pianzola et al., Development 141, 1915-1926. doi: 10.1242/dev.099432
Dix et al., J. Cell Biol. 202, 479–494.
Vazquez-Pianzola et al., Dev. Biol. 357, 404-418. doi:10.1016/j.ydbio.2011.07.009
Koch et al., PLoS ONE 4(2): e4552.
Cavey et al., Development 132, 459-468.
Houalla et al., Mech. Dev. 122, 97-108.
Paré and Suter, J Cell Sci. 113, 2119-2127.
Swan et al., Nature Cell Biology 1, p444-449.
Stuurman et al., Eur. J. Cell Biol. 78, 278-287.
Swan and Suter, Development 122, 3577-3586.
Ran et al., Development 120, 1233-1242.
Suter and Steward, Cell 67, 917-926.
Suter et al., Genes & Dev. 3, 1957-1968.
Börner et al., Developmental Biology 411, 217–230.
Murakami et al., Current Biology 26, 972-980.
Urwyler et al., Biology Open, doi: 10.1242/bio.20122154.
Claußen et al., Genetics 174, 1337–1347.
Cell cycle control: Cdk7 and Xpd
Subunits of the TFIIH complex participate in transcription, nucleotide excision repair (NER) and cell cycle control. One of them, Cdk7, phosphorylates transcriptional and cell cycle targets. Another one, Xpd, can co-ordinate different processes by recruiting or controlling the sub-complex containing the Cdk7 kinase and by dispatching it towards and away from different cellular substrates. In this way Xpd negatively regulates the cell cycle function of Cdk7, the Cdk activating kinase (CAK) activity. Amazingly, Xpd also co-ordinates mitotic cycles between thousands of somatic embryonic nuclei that share one common cytoplasm. Furthermore, Drosophila and human xpd are essential for proper spindle dynamics and for segregation of the chromosomes at the exit from mitosis, and lack of xpd causes chromosomal instability (CIN), a hallmark of cancer. These novel xpd functions are independent of its NER- and transcription functions, and defects in these functions may contribute to the high cancer incidence found in XP patients.
Analyses of the cell cycle, spindle and growth functions of xpd are interesting for basic research because they reveal novel basic cellular control mechanisms. In addition, the work seems also highly relevant to the understanding of the XP syndrome of human XPD patients, in particular to the understanding of the high cancer risk associated with a specific subset of the mutations.
In addition to xpd, we also identified a couple of other genes that interact with cdk7 genetically. With studies analogous to the our Xpd work we also explore what these genes tell us about cross talks between physiological activities of the cell and the cell cycle regulatory and growth control network.
Cell cycle control: Cdk7 and Xpd
The protein kinase Cdk7 is an essential activator of the mitotic cell cycle kinase Cdk1. However, it also participates in other physiological activities, particularly in transcription. These two processes are mutually exclusive and Cdk7 switches from one function to the other during the cell cycle. We found that Xpd plays a role in directing the Cdk7 activity towards the correct target during the cell cycle. Indeed, Xpd can be found in complexes with Cdk7 and it appears to act as a dispatcher that sends the Cdk7 kinase towards specific cellular substrates or prevents it from targeting a substrate class at particular phases of the cell cycle. In this way Xpd negatively regulates the cell cycle function of Cdk7, the phosphorylation of Cdks, and it recruits Cdk7 into the TFIIH complex where it functions in transcription. This attributes an apparently direct cell cycle function to Xpd, in addition to its roles in DNA repair and transcription.
Studying the cell cycle function of Xpd we found that Xpd is essential for the proper dynamics of the mitotic spindle and for segregation of the chromosomes at the exit from mitosis. Lack of Xpd and mutations in xpd cause chromosomal instability (CIN), a hallmark of cancer. Furthermore, Drosophila Xpd coordinates mitotic cycles between thousands of embryonic nuclei that share a common cytoplasm. Using Drosophila as experimental model system, we were able to show how mutations identified in human XPD patients affect the function of Xpd and how this might contribute to the human XPD phenotypes. Why does Xpd control Cdk7 only during specific phases of the cell cycle? Who regulates Xpd? These are the questions we are presently addressing.
Selected primary research articles:
Stettler et al., Disease Models & Mechanisms 8, 81-91 doi:10.1242/dmm.016907.
Cameroni et al., Cell Division, 5, 24
Li et al., PLoS Genet 6, e1000876.
Schwartz et al., Mol. Cell. Biol. 23, 6876-6886.
Chen and Suter Cell Cycle 2; 503-506.
Chen et al., Nature 424: 228-232.
Masrouha et al., Genetics 163: 973–982.
Larochelle et al., EMBO J. 20; 3749-3759.
Larochelle et al., Genes & Dev. 12, 370-381.
PheRS and multifunctional proteins
Aminoacyl-tRNA synthetases (aaRSs) ligate amino acids to their cognate tRNAs, allowing them to decode the triplet code during translation. For accurate decoding it is imperative that the enzyme recognizes the appropriate amino acid and that it charges the proper tRNA with the correct amino acid. The enzyme that charges tRNAPhe with the amino acid Phe, PheRS, uses a 2-step process to achieve a high decoding accuracy. A first sieve is an amino acid binding pocket that is too small for the similar amino acid Tyr. In addition, there is a proof reading mechanism that can sieve out the wrongfully activated or charged Tyr.
Mutations in many different human aaRSs cause human diseases (particularly neurodegenerative diseases) and aaRSs have also been linked to signaling and cancer. Interestingly, many aaRSs also perform additional functions in the cell, unrelated to their aminoacylation function. It is therefore not known how these aaRS mutations lead to the disease. In order to assess the importance of aminoacylation fidelity in multicellular organisms, we generated an amino-acid double-sieving model in Drosophila melanogaster using phenylalanyl-tRNA synthetase (PheRS). Double-sieving-defective mutations dramatically misacylate non-cognate Tyr, induce protein mistranslation and cause endoplasmic reticulum stress in flies. Mutant adults exhibit severe defects, including loss of neuronal cells, impaired locomotive performance, shortened lifespan and smaller organ size. The mutations also reduce cell proliferation and promote cell death. We are now trying to identify the non-canonical functions of Drosophila PheRS.
Lu et al., Nature Commun 5:5650 | DOI: 10.1038/ncomms6650.
Lu et al., Fly, 9, 53-61, DOI: 10.1080
Dolde et al., Advances in Biology, Volume 2014, Article ID 274196
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- Name / Titel
- Dr. Paula Vasquez
- Wissenschaftliche Mitarbeiterin
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Vazquez Pianzola, Maria Paula; Schaller, Bogdan; Colombo, Martino; Beuchle, Dirk; Neuenschwander, Samuel; Marcil, Anne; Bruggmann, Rémy; Suter, Beat (2017). The mRNA transportome of the BicD / Egl transport machinery. RNA biology, 14(1), pp. 73-89. Taylor and Francis 10.1080/15476286.2016.1251542
Rashpa, Ravish; Vazquez Pianzola, Maria Paula; Colombo, Martino; Hernandez, Greco; Beuchle, Dirk; Berger, Fabienne Chantal; Peischl, Stephan; Bruggmann, Rémy; Suter, Beat (2017). Cbp80 is needed for the expression of piRNA components and piRNAs. PLoS ONE, 12(7), e0181743. Public Library of Science 10.1371/journal.pone.0181743
Vazquez Pianzola, Maria Paula; Suter, Beat; Hernández, Greco (2016). Evolution of the Molecules Coupling mRNA Transport with Translational Control in Metazoans. In: Hernández, Greco; Jagus, Rosemary (eds.) Evolution of the Protein Synthesis Machinery and Its Regulation (pp. 531-546). Springer 10.1007/978-3-319-39468-8_21
Murakami, Kazuma; Yurgel, Maria E; Stahl, Bethany A; Masek, Pavel; Mehta, Aradhana; Heidker, Rebecca; Bollinger, Wesley; Gingras, Robert M; Kim, Young-Joon; Williams, Jack; Suter, Beat; DiAngelo, Justin R; Keene, Alex C (2016). translin Is Required for Metabolic Regulation of Sleep. Current Biology, 26(7), pp. 972-980. Cell Press 10.1016/j.cub.2016.02.013
Börner, Kenneth; Jain, Dhawal; Vazquez Pianzola, Maria Paula; Vengadasalam, Sandra; Steffen, Natascha; Fyodorov, Dmitry V; Tomancak, Pavel; Konev, Alexander; Suter, Beat; Becker, Peter B (2016). A role for tuned levels of nucleosome remodeler subunit ACF1 during Drosophila oogenesis. Developmental biology, 411(2), pp. 217-230. Elsevier 10.1016/j.ydbio.2016.01.039
Stettler, Karin; Li, Xiaoming; Sandrock, Björn; Braga, Sophie Marie-Pierre; Heller, Manfred; Dümbgen, Lutz; Suter, Beat (2015). A Drosophila XPD model links cell cycle coordination with neuro-development and suggests links to cancer. Disease models & mechanisms, 8(1), pp. 81-91. Company of Biologists Ltd. 10.1242/dmm.016907
Lu, Jiongming; Marygold, Steven J; Gharib, Walid H; Suter, Beat (2015). The aminoacyl-tRNA synthetases of Drosophila melanogaster. Fly, 9(2), pp. 53-61. Taylor & Francis 10.1080/19336934.2015.1101196
Lu, Jiongming; Bergert, Martin; Walther, Anita; Suter, Beat (2014). Double-sieving-defective aminoacyl-tRNA synthetase causes protein mistranslation and affects cellular physiology and development. Nature communications, 5(5650), pp. 1-13. Nature Publishing Group 10.1038/ncomms6650
Dolde, Christine; Lu, Jiongming; Suter, Beat (2014). Cross talk between cellular regulatory networks mediated by shared proteins. Advances in Biology, 2014, pp. 1-12. Hindawi Publishing Corporation 10.1155/2014/274196
Vazquez Pianzola, Maria Paula; Adam, Jacqueline; Haldemann, Dominique; Hain, Daniel; Suter, Beat; Urlaub, Henning (2014). Clathrin heavy chain plays multiple roles in polarizing the Drosophila oocyte downstream of Bic-D. Development, 141(9), pp. 1915-1926. Company of Biologists Limited 10.1242/dev.099432
Dix, Carly I; Soundararajan, HC; Dzhindzhev, NS; Begum, F; Suter, Beat; Ohkura, H; Stephens, E; Bullock, SL (2013). Lissencephaly-1 promotes the recruitment of dynein and dynactin to transported mRNAs. Journal of cell biology, 202(3), pp. 479-494. Rockefeller Institute Press 10.1083/jcb.201211052
Vazquez-Pianzola, Paula; Suter, Beat (2012). Conservation of the RNA Transport Machineries and Their Coupling to Translation Control across Eukaryotes. Comparative and functional genomics, 2012, p. 287852. New York, N.Y.: Hindawi 10.1155/2012/287852
Urwyler, Olivier; Cortinas-Elizondo, Fabiola; Suter, Beat (2012). Drosophila sosie functions with beta(H)-Spectrin and actin organizers in cell migration, epithelial morphogenesis and cortical stability. Biology open BiO, 1(10), pp. 994-1005. Cambridge: Company of Biologists 10.1242/bio.20122154
Vazquez-Pianzola, Paula; Urlaub, Henning; Suter, Beat (2011). Pabp binds to the osk 3'UTR and specifically contributes to osk mRNA stability and oocyte accumulation. Developmental biology, 357(2), pp. 404-418. San Diego, Calif.: Elsevier 10.1016/j.ydbio.2011.07.009
Cameroni, Elisabetta; Stettler, Karin; Suter, Beat (2010). On the traces of XPD: cell cycle matters - untangling the genotype-phenotype relationship of XPD mutations. Cell division, 5(1), p. 24. London: BioMed Central 10.1186/1747-1028-5-24
Li, Xiaoming; Urwyler, Olivier; Suter, Beat (2010). Drosophila Ypd Regulates Cdk7 Localization, Mitotic Kinase Activity, Spindle Dynamics, and Chromosome Segregation. PLoS genetics, 6(3), e1000876. San Francisco, Calif.: Public Library of Science 10.1371/journal.pgen.1000876
Koch, Rafael; Romana, Ledermann; Urwyler, Olivier; Heller, Manfred; Suter, Beat (2009). Systematic Functional Analysis of BicD Serine Phosphorylation and Intragenic Suppression of a Female Sterile Allele of BicD. PLoS ONE, 4(2), e4552. Lawrence, Kans.: Public Library of Science 10.1371/journal.pone.0004552
Kissler, A. E.; Pettersson, N.; Frolich, A.; Sigrist, S. J.; Suter, Beat (2009). Drosophila cdk5 is Needed for Locomotive Behavior and NMJ Elaboration, but Seems Dispensable for Synaptic Transmission. Developmental neurobiology, 69(6), pp. 365-377. Hoboken, N.J.: Wiley Periodicals, Inc. 10.1002/Dneu.20711
Levine, Sylvia; Sunday, Suchot; Dorig, Ruth; Suter, Beat; Lasko, Paul (2007). Genetic maps of the proximal half of chromosome arm 2L of Drosophila melanogaster. Genome, 50(2), pp. 137-41. Ottawa: National Research Council of Canada 10.1139/G06-149
Vazquez-Pianzola, Paula; Hernandez, Greco; Suter, Beat; Rivera-Pomar, Ronaldo (2007). Different modes of translation for hid, grim and sickle mRNAs in Drosophila. Cell death and differentiation, 14(2), pp. 286-295. Basingstoke: Nature Publishing Group 10.1038/sj.cdd.4401990
Urwyler, Olivier; Zhang, Li; Li, Xiaoming; Imboden, Johann; Suter, Beat (2007). Tissue-dependent subcellular localization of Drosophila arginine methyl-transferase 4 (DART4), a coactivator whose overexpression affects neither viability nor differentiation. Differentiation, 75(8), pp. 757-65. Oxford: Elsevier 10.1111/j.1432-0436.2007.00175.x
Claussen, Maike; Koch, Rafael; Jin, Zhao-Yang; Suter, Beat (2006). Functional characterization of Drosophila Translin and Trax. Genetics, 174(3), pp. 1337-1347. Bethesda, Md.: Genetics Society of America 10.1534/genetics.106.063016
Cavey, Matthieu; Hijal, Sirine; Zhang, Xiaolan; Suter, Beat (2005). Drosophila valois encodes a divergent WD protein that is required for Vasa localization and Oskar protein accumulation. Development, 132(3), pp. 459-468. Company of Biologists Limited 10.1242/dev.01590
Claussen, Maike; Suter, Beat (2005). BicD Dependent Localization Processes: from Drosophila Development to Human Cell Biology. Annals of anatomy - Anatomischer Anzeiger, 187(5-6), pp. 539-553. Elsevier 10.1016/j.aanat.2005.07.004
Houalla, Tarek; Vuong, Dac Hien; Ruan, Wenjing; Suter, Beat; Rao, Yong (2005). The Ste20-like kinase misshapen functions together with Bicaudal-D and dynein in driving nuclear migration in the developing drosophila eye. Mechanisms of development, 122(1), pp. 97-108. Elsevier 10.1016/j.mod.2004.08.005
Christopher, Schuetze; Peters, Michelle; Jia-Jen, Duong; Matthieu, Cavey; Dörig, Ruth; Lasko, Paul; Suter, Beat (2004). Map positions of third chromosomal female sterile and lethal mutations of Drosophila melanogaster. Genome, 47(5), pp. 832-838. National Research Council of Canada 10.1139/g04-052
Alarco, Anne-Marie; Marcil, Anne; Chen, Jian; Suter, Beat; Thomas, David; Whiteway, Malcolm (2004). Immune-Deficient Drosophila melanogaster: A Model for the Innate Immune Response to Human Fungal Pathogens. Journal of immunology, 172(9), pp. 5622-5628. American Association of Immunologists 10.4049/jimmunol.172.9.5622
BOULANGER, Marie-Chloé; MIRANDA, Tina Branscombe; Steven, CLARKE; DI FRUSCIO, Marco; Suter, Beat; LASKO, Paul; RICHARD, Stéphane (2004). Characterization of the Drosophila protein arginine methyltransferases DART1 and DART4. Biochemical journal, 379(Pt2), pp. 283-289. Portland Press 10.1042/BJ20031176
Chen, Jian; Larochelle, Stéphane; Li, Xiaoming; Suter, Beat (2003). Xpd/Ercc2 regulates CAK activity and mitotic progression. Nature, 424(6945), pp. 228-232. Macmillan Journals Ltd. 10.1038/nature01746
Masrouha, Nisrine; Yang, Long; Hijal, Sirine; Larochelle, Stéphane; Suter, Beat (2003). The Drosophila chk2 gene loki is essential for embryonic DNA double-strand-break checkpoints induced in S phase or G2. Genetics, 163(3), pp. 973-982. Genetics Society of America
Schwartz, Brian E.; Larochelle, Stephane; Suter, Beat; Lis, John T (2003). Cdk7 is required for full activation of Drosophila heat shock genes and RNA polymerase II phosphorylation in vivo. Molecular and cellular biology, 23(19), pp. 6876-6886. American Society for Microbiology 10.1128/MCB.23.19.6876–6886.2003