Gruber Lab

The Gruber lab investigates molecular machines that act on DNA to ensure the integrity of genetic information by maintaining chromosomal DNA and defending against invasive DNA elements such as viruses and plasmids.

• How are genomes organized?
• How are chromosomes segregated during cell division?
• How is DNA damage repaired?
• How is non-self DNA recognized and eliminated?

We are part of the Department of Fundamental Microbiology (@DMF_UNIL) at the Faculty of Biology and Medicine, the University of Lausanne. Find out who we are and what we do. Follow us @Gruber_Lausanne @GruberLab.bsky.social.

Organizing DNA for Segregation and Repair

Cells organize and compact the long and flexible DNA molecules within chromosomes to precisely control gene expression patterns, to support DNA repair processes and DNA recombination events, and to faithfully segregate chromosomes during cell division. However, the underlying principles of chromosome folding and how they impact genome expression and maintenance are still poorly understood. Our research aims to shed light on these fundamental processes by studying microbial model organisms including bacteria and budding yeast. 

Key factors in chromosome folding: The SMC ATPase complexes

Our research focuses on the multi-subunit SMC ATPase complexes, which play a crucial role in organizing chromosomes by bringing together distal segments of a chromosome. The current theory is that these complexes are responsible for actively extruding DNA loops through the use of the SMC DNA motor. These motors are able to take large steps along the DNA and bypass obstacles, while also maintaining directionality over long periods of time. To gain a better understanding of the mechanisms behind this process, we are studying bacterial SMC complexes and the yeast Smc5/6 complex using biochemical techniques and cryo-electron microscopy at the Dubochet Center for Imaging in Lausanne (@DCI_EM). Our work has led to the development of the DNA segment capture model, which we are now testing.

SMC Wadjet systems in bacterial immunity

Wadjet systems are derivative SMC complexes that play a role in bacterial immunity, rather than in chromosome folding. We and others have recently shown that these JetABCD complexes eliminate plasmids by cleaving the DNA. We are interested in understanding how the Wadjet complexes specifically recognize and target smaller circular DNA molecules, while sparing the host chromosome from processing. The eukaryotic Smc5/6 complexes have been shown to play an apparently related role in defense against infection by viruses (HBV, EBV and others). We are working to understand how these activities in viral and plasmid defense are related to one another and to the more canonical functions of SMC complexes in genome folding and maintenance. Recently, we have also started investigating other bacterial defense systems that act on DNA and share similarities with chromosomal machinery.

ParABS & cellular regulation

ParABS systems are important for promoting chromosome segregation and plasmid maintenance in many bacteria and some archaea, as well as for supporting additional regulatory functions within the cell. These systems work by binding ParB proteins to centromeric parS sequences to form large nucleoprotein complexes that interact with specific ATPases (ParA and Smc) to partition plasmid and chromosome copies. We have recently discovered that ParB proteins are enzymes – the first known CTP hydrolases – which form DNA sliding clamps that self-load onto parS DNA. We are particularly interested in how the combination of ParB CTP binding and hydrolysis with ParA and Smc ATPases promotes chromosome organization and segregation in bacteria.

Our approach

A deep understanding of the architecture and structure of macromolecular assemblies is often essential for gaining a mechanistic understanding of their function. Our research combines genetics, molecular and cell biology, biochemistry, and structural biology to reveal the molecular basis of protein function and cellular activity. We use a range of biophysical techniques and structural biology to investigate protein-DNA complexes and DNA organization in vitro, as well as in vivo techniques such as ChIP-Seq, Hi-C, directed or random mutagenesis, and site-specific cross-linking. By combining these approaches, we hope to gain insights into the underlying mechanisms of these complex systems.

New focus?

We are always open to exploring new areas of research, including the roles of other SMC and SMC-like proteins (such as Rad50 and RecN) in maintaining DNA integrity in both bacteria and eukaryotes.

	Hammam Antar hammam.antar[a]unil.ch +41-21-692-5611 2017-2019 – M. Sc. Immunology, Microbiology & Infectious Diseases (IMD) – University of Grenoble Alpes, France
	Joe Dickinson joe.dickinson[a]unil.ch +41-21-692-5611 2020-2022 – M. Sc. Molecular Life Sciences – University of Lausanne, Switzerland
	Ophélie Gosselin ophélie.gosselin[a]unil.ch +41-21-692-5611 2017-2019 – M. Sc. Biochemistry, Molecular and Cellular Biology – UC Louvain, Belgium
	Stephan Gruber Short CV stephan gruber unil ch +41-21-692-5601 OrcID, WebOfScience, ResearchGate, Google Scholar
	Maya Houmel maya.houmel[a]unil.ch +41-21-692-5611 2018-2020 – M. Sc. Genetics,  Magistère Européen de Génétique, University of Paris, France
	Yan Li yan.li[a]unil.ch +41-21-692-5611 2015-2019 – Ph. D. , Panne lab, EMBL Grenoble, France 2010-2013 – M. Sc. Structural Biology – University of the Chinese Academy of Sciences, Shanghai, China
	Hon-Wing Liu – EMBO Postdoc hon-wing.liu[a]unil.ch +41-21-692-5611 2015-2020 – Ph. D. , Uhlmann lab, The Francis Crick Institute, London, UK 2011-2015 – MA M. Sc. Biochemistry – University of Cambridge, UK
	Florian Roisné-Hamelin – EMBO Postdoc florian.roisne-hamelin[a]unil.ch +41-21-692-5611 2016-2021 – Ph. D., Marcand lab,  Institut de Biologie François Jacob, CEA, Paris, France 2014-2016 – M. Sc. Genetics & Cell Biology- University of Lyon 1, France
	Michael Taschner – Research scientist michael.taschner[a]unil.ch +41-21-692-5611 2010-2017 – Postdoc – Lorentzen lab, Max Planck Institute of Biochemistry, Munich, Germany 2005-2009 – Ph. D. Biochemistry – Svejstrup lab, UCL, UK 2000-2004 – Diploma Biology – University of Vienna, Austria

Former lab members

Anna Anchimiuk, PhD student, now @ Roche, Switzerland

Alrun Basfeld, Intern, now @ WuXi Biologics, Leverkusen, Germany

Mélanie Beraud, Postdoctoral fellow, now senior technician @ Université de Mons, Mons, Belgium

Martin Blettinger, Technician, now @ Hexal Sandoz, Munich, Germany

Florian Bock, PhD student, now @ Venning lab, Lausanne, Switzerland

Frank Bürmann, PhD student, now Welcome Trust Career Development Fellow @ University of Oxford, UK

Marie-Laure Diebold-Durand, Postdoctoral fellow, now @IGBMC Strasbourg, France

Alexandre Durand, Postdoctoral fellow, now EM Facility Manager – Inserm @IGBMC Strasbourg, France

Victor Gimenez-Oya, Postdoctoral fellow, now @ LMU Munich, Germany

Franziska Kemter, Postdoctoral fellow

Daniel Meyer, Technician, now @ Max Planck Institute for Quantum Optics, Munich, Germany

Anita Minnen, PhD student, now Postdoc @ Max Planck Institute of Biochemistry, Munich, Germany

Laura Ruiz Avila, Postdoctoral fellow, now @ Extedo, Munich, Germany

Jae Shin, Postdoc, now Senior Researcher @ NanoLund, Sweden

Young-Min Soh, Postdoctoral fellow, now fellow @ NIH, US

Chris Toseland, Postdoctoral fellow, Professor, University of Sheffield, UK

Roberto Vazquez Nunez, PhD student, now Postdoctoral fellow @ MIT, US

Larissa Wilhelm, PhD student, now @ Novartis, Vienna, Austria

Preprints

• Janissen R., Barth R., Davidson I.F., Taschner M., Gruber S., Peters J.M., Dekker C.*, 2024. All eukaryotic SMC proteins induce a twist of -0.6 at each DNA-loop-extrusion step.
  preprint, 2024 [BioRxiv]
• Barth R., Davidson I.F., van der Torre J., Taschner M., Gruber S., Peters J.M., Dekker C.*, 2023. SMC motor proteins extrude DNA asymmetrically and contain a direction switch.
  preprint, 2023 [BioRxiv]

2024

• Roisné-Hamelin F., Liu H. W., Taschner M., Li Y., Gruber S.*, 2024. Structural basis for plasmid restriction by SMC JET nuclease.
  Molecular Cell
  Vol 84, Issue 5 [Pubmed] [DOI]
  preprint 2023 [BioRxiv]
• Tišma M., Bock F.P., Kerssemakkers J., Antar H., Japaridze A., Gruber S., Dekker C.*, 2024. Direct observation of a crescent-shape chromosome in expanded Bacillus subtilis cells.
  Nature Communications
  Vol 15, 2737 [Pubmed] [DOI]
  preprint 2023 [BioRxiv]
• Liu X., Van Maele L., Matarazzo L., Soulard D., Duarte da Silva V.A., de Bakker V., Dénéréaz J., Bock F.P., Taschner M., Ou J., Gruber S., Nizet V., Sirard J.-C.*, Veening J.-W.*, 2023. A conserved antigen induces respiratory Th17-mediated serotype-independent protection against pneumococcal superinfection.
  Cell Host & Microbe
  Vol 32, 1-11 [Pubmed] [DOI] [free link]
  preprint 2023 [BioRxiv]
• Tišma M., Kaljevic J., Gruber S., Le T.B.K., Dekker C.*, 2024. Connecting the dots: key insights on ParB for chromosome segregation from single-molecule studies.
  FEMS Microbiol Rev
  Vol 48 (1) [Pubmed] [DOI]

2023

• Taschner M., Gruber S.*, 2023. DNA segment capture by Smc5/6 holo-complexes.
  Nature Structural & Molecular Biology
  10.1038/s41594-023-00956-2 [Pubmed] [DOI]
  preprint 2022 [BioRxiv]
• Liu H. W., Roisné-Hamelin F., Gruber S.*, 2023. SMC-based immunity against extrachromosomal DNA elements.
  Biochemical Society Transactions
  BST20221395 [Pubmed] [DOI]
• Antar H., Gruber S.*, 2023. VirB, a transcriptional activator of virulence in Shigella flexneri, uses CTP as a cofactor.
  Communications Biology
  6:1024 [Pubmed] [DOI]
  preprint 2023 [BioRxiv]
• Tišma M., Janissen R., Antar H., Martin Gonzalez A., Barth R., Beekman T., van der Torre J., Michieletto D., Gruber S., Dekker C.*, 2023. Dynamic ParB-DNA interactions initiate and maintain a partition condensate for bacterial chromosome segregation.
  Nucleic Acids Research
  gkad868 [Pubmed][DOI]
  preprint 2023  [BioRxiv]

2022

• Liu H. W., Roisné-Hamelin F., Beckert B., Li Y., Myasnikov A., Gruber S.*, 2022. DNA-measuring Wadjet SMC ATPases restrict smaller circular plasmids by DNA cleavage.
  Molecular Cell
  Vol 82, Issue 24 [Pubmed] [DOI]
  preprint, 2022 [BioRxiv]
• Roberts D. M., Anchimiuk A., Kloosterman T. G., Murray H., Wu L. J, Gruber S., Errington J.*, 2022. Chromosome remodelling by SMC/Condensin in B. subtilis is regulated by Soj/ParA during growth and sporulation.
  PNAS
  Vol 40, Issue 9 [Pubmed] [DOI]
  preprint, 2021 [BioRxiv]
• Bock F. P., Liu H. W., Anchimiuk A., Diebold-Durand M.-L., Gruber S.*, 2022. A joint-ParB interface promotes Smc DNA recruitment.
  Cell Reports
  Vol 119, Issue 41 [Pubmed] [DOI]
  preprint, 2021 [BioRxiv]
• Tisma M., Panoukidou M., Antar H., Soh Y.-M., Barth R., Pradhan B., van der Torre J., Michieletto D., Gruber S., Dekker C.*, 2022. ParB proteins can bypass DNA-bound roadblocks by dimer-dimer recruitment.
  Science Advances
  Vol 8, Issue 26 [Pubmed] [DOI]
  preprint, 2021 [BioRxiv]
• Nomidis S.S., Carlon E., Gruber S., Marko J. F.*, 2022. DNA tension-modulated translocation and loop extrusion by SMC complexes revealed by molecular dynamics simulations.
  Nucleic acids research
  gkac268 [Pubmed] [DOI]
  preprint, 2021 [BioRxiv]

2021

• Antar H.°, Soh Y.-M.°, Zamuner S., Bock F. P., Anchimiuk A., De Los Rios P., Gruber S.*, 2021. Relief of ParB autoinhibition by parS DNA catalysis and ParB recycling by CTP hydrolysis promote bacterial centromere assembly.
  Science Advances
  Vol 7, Issue 41 [Pubmed] [DOI]
  preprint, 2021 [BioRxiv]
• Taschner M., Basquin J., Steigenberger B., Schaefer I., Soh Y.-M., Basquin C., Lorentzen E., Räschle M., Scheltema R. A., Gruber S.*, 2021. Nse5/6 inhibits the Smc5/6 ATPase and modulates DNA substrate binding.
  EMBO Journal
  e107807 [Pubmed] [DOI]
  preprint, 2021 [BioRxiv]
• Anchimiuk A., Lioy V. S., Minnen A., Boccard F., Gruber S.*, 2021. A low Smc flux avoids collisions and facilitates chromosome organization in B. subtilis.
  eLife
  65467 [Pubmed] [DOI]
  preprint, 2020 [BioRxiv]
• Gallay C.°, Sanselicio S.°, Anderson M. E.,  Soh Y.-M., Liu X., Stamsas G. A., Pelliciari S., van Raaphorst R., Dénéréaz J., Kjos M., Murray H., Gruber S., Grossman A. D., Veening J.-W.*, 2021. CcrZ is a pneumococcal spatiotemporal cell cycle regulator that interacts with FtsZ and controls DNA replication.
  Nature Microbiology
  021-00949-1 [Pubmed] [DOI]
  preprint, 2019 [BioRxiv]
• Vazquez Nunez R. J.°, Polyhach Y.°, Soh Y.-M., Jeschke G., Gruber S.*, 2021. Gradual opening of Smc arms in prokaryotic condensin.
  Cell Reports
  35(4) 109051 [Pubmed] [DOI]
  preprint, 2021 [BioRxiv]

2020

• Soh Y.-M., Basquin J., Gruber S.*, 2020. A rod conformation of the Pyrococcus furiosus Rad50 coiled coil.
  Proteins
  prot.26005 [Pubmed] [DOI] [PDB: 6ZFF]
  preprint, 2020 [BioRxiv]
• Metwaly G., Wu Y., Peplowska K., Röhrl J., Soh Y.-M., Bürmann F., Gruber S., Storchova Z.*, 2020. Phospho-regulation of the Shugoshin-Condensin interaction at the centromere in budding yeast.
  PLOS Genetics
  16(8) [Pubmed] [DOI]
  preprint, 2019 [BioRxiv]
• Jeon J.-H., Lee H.-S., Shin H.-C., Kwak M.-J., Kim Y.-G., Gruber S. and Oh B.-H.*, 2020. Evidence for binary Smc complexes lacking kite subunits in archaea.
  IUCrJ
  7(2) [Pubmed] [DOI]
• Prassler J., Simon F., Ecke M., Gruber S. and Gerisch G.* 2020. Decision making in phagocytosis.
  AEMB
  1246:71-81 [Pubmed] [DOI] [PDF]

2019

• Soh Y.-M., Davidson I. F., Zamuner S., Basquin J., Taschner M., Bock F. P., Veening J.-W., De Los Rios P., Peters J.-M., Gruber S.*, 2019. Self-organization of parS centromeres by the ParB CTP hydrolase.
  Science
  360(6469) p. 1129-1133 [Pubmed] [DOI] [Free] [PDB: 6SDK] [PDF] [F1000_recommendations] [Perspective by Barbara Funnell]
• Vazquez Nunez R.°, Ruiz Avila L. B.°, Gruber S.*, 2019. Transient DNA occupancy of the SMC interarm space in prokaryotic condensin.
  Molecular Cell
  75(5) p. 1-15 [Pubmed] [DOI] [Free full-text] [Preview by Tomoko Nishiyama]
  preprint, 2018 [BioRxiv]
• Marko J. F.*, De Los Rios P., Barducci A., Gruber S., 2019. DNA-segment-capture model for loop extrusion by structural maintenance of chromosome (SMC) protein complexes.
  Nucleic Acids Research
  gkz497 [Pubmed] [DOI]
  preprint, 2018 [BioRxiv]
• Diebold-Durand M.-L., Bürmann F., Gruber S.*, 2019. High-throughput allelic replacement screening in Bacillus subtilis.
  Methods in Molecular Biology
  2004 p. 49-61 [Pubmed] [DOI] [PDF]

2018

• Pfeiffer F., Zamora-Lagos M.-A., Blettinger M., Yeroslavic A., Dahl A., Gruber S.*, Habermann B. H.*, 2018. The complete and fully assembled genome sequence of Aeromonas salmonicida subsp. pectinolytica and its comparative analysis with other Aeromonas species: investigation of the mobilome in environmental and pathogenic strains.
  BMC Genomics
  19(1):20 [Pubmed] [DOI]
• Gruber S., 2018. SMC complexes sweeping through the chromosome: Going with the flow and against the tide.
  Current Opinion in Microbiology
  42:96-103 [Pubmed] [DOI] [PDF]
• Stockmar I., Feddersen H., Cramer K., Gruber S., Jung K., Bramkamp M.*, Shin J. Y.* 2018. Optimization of sample preparation and green color imaging using the mNeonGreen fluorescent protein in bacterial cells for photoactivated localization microscopy.
  Scientific Reports
  8(1): 10137 [Pubmed] [DOI]

2017

• Diebold-Durand M.-L.°, Lee H.°, Ruiz Avila L.°, Noh H., Shin H.-C., Im H., Bock F. P., Bürmann F., Durand A., Basfeld A., Ham S., Basquin J., Oh B.-H.*, Gruber S.*, 2017. Structure of full-length SMC and rearrangements required for chromosome organization.
  Molecular Cell
  67(2) p. 334-347 [DOI] [Web of Science] [Pubmed] [PDB: 5NMO, 5NNV]
• Bürmann F., Basfeld A., Vazquez Nunez R., Diebold-Durand M.-L., Wilhelm L., Gruber S.*, 2017. Tuned SMC arms drive chromosomal loading of prokaryotic condensin.
  Molecular Cell
  65(5) p. 861-872 [DOI] [Web of Science] [Pubmed] [F1000 recommendation]
• Gruber S., 2017. Shaping Chromosomes by DNA Capture and Release: Gating the SMC Rings.
  Current Opinion in Cell Biology
  46:87-93 [DOI] [Web of Science] [Pubmed] [PDF]
• Wilhelm L., Gruber S.*, 2017. A Chromosome Co-Entrapment Assay to Study Topological Protein–DNA Interactions.
  Methods in Molecular Biology
  1624 p. 117-126 [DOI] [Web of Science] [Pubmed] [PDF]. An updated version of the protocol (using agarose microbeads instead of agarose plugs) is available here: [DOI].

2016