Christian H Haering

European Molecular Biology Laboratory, Heidelburg, Baden-Württemberg, Germany

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Publications (28)318.39 Total impact

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    Yuri Frosi · Christian H Haering ·
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    ABSTRACT: Although condensin protein complexes have long been known for their central role during the formation of mitotic chromosomes, new evidence suggests they also act as global regulators of genome topology during all phases of the cell cycle. By controlling intra-chromosomal and inter-chromosomal DNA interactions, condensins function in various contexts of chromosome biology, from the regulation of transcription to the unpairing of homologous chromosomes. This review highlights recent advances in understanding how these global functions might be intimately linked to the molecular architecture of condensins and their extraordinary mode of binding to DNA. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.
    Current opinion in cell biology 06/2015; 34. DOI:10.1016/ · 8.47 Impact Factor
  • Marc Kschonsak · Christian H. Haering ·
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    ABSTRACT: How eukaryotic genomes are packaged into compact cylindrical chromosomes in preparation for cell divisions has remained one of the major unsolved questions of cell biology. Novel approaches to study the topology of DNA helices inside the nuclei of intact cells, paired with computational modeling and precise biomechanical measurements of isolated chromosomes, have advanced our understanding of mitotic chromosome architecture. In this Review Essay, we discuss - in light of these recent insights - the role of chromatin architecture and the functions and possible mechanisms of SMC protein complexes and other molecular machines in the formation of mitotic chromosomes. Based on the information available, we propose a stepwise model of mitotic chromosome condensation that envisions the sequential generation of intra-chromosomal linkages by condensin complexes in the context of cohesin-mediated inter-chromosomal linkages, assisted by topoisomerase II. The described scenario results in rod-shaped metaphase chromosomes ready for their segregation to the cell poles. © 2015 The Authors. Bioessays published by WILEY Periodicals, Inc.
    BioEssays 05/2015; 37(7). DOI:10.1002/bies.201500020 · 4.73 Impact Factor
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    ABSTRACT: The advent of genome-wide RNAi-based screens puts us in the position to identify genes for all functions human cells carry out. However, for many functions, assay complexity and cost make genome-scale knockdown experiments impossible. Methods to predict genes required for cell functions are therefore needed to focus RNAi screens from the whole genome to the most likely candidates. While different bioinformatics tools for gene function prediction exist, they lack experimental validation and are therefore rarely used by experimentalists. To address this, we developed an effective computational gene selection strategy that represents public data about genes as graphs and then analyses these graphs using kernels on graph nodes to predict functional relationships. To demonstrate its performance, we predicted human genes required for a poorly understood cellular function, mitotic chromosome condensation, and experimentally validated the top 100 candidates with a focused RNAi screen by automated microscopy. Quantitative analysis of the images demonstrated that the candidates were indeed strongly enriched in condensation genes including the discovery of several new factors. By combining bioinformatics prediction with experimental validation, our study shows that kernels on graph nodes are a powerful tool to integrate public biological data and predict genes involved in cellular functions of interest.
    Molecular biology of the cell 06/2014; 25(16):2522-2536. DOI:10.1091/mbc.E13-04-0221 · 4.47 Impact Factor
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    ABSTRACT: Condensin complexes have central roles in the three-dimensional organization of chromosomes during cell divisions, but how they interact with chromatin to promote chromosome segregation is largely unknown. Previous work has suggested that condensin, in addition to encircling chromatin fibers topologically within the ring-shaped structure formed by its SMC and kleisin subunits, contacts DNA directly. Here we describe the discovery of a binding domain for double-stranded DNA formed by the two HEAT-repeat subunits of the Saccharomyces cerevisiae condensin complex. From detailed mapping data of the interfaces between the HEAT-repeat and kleisin subunits, we generated condensin complexes that lack one of the HEAT-repeat subunits and consequently fail to associate with chromosomes in yeast and human cells. The finding that DNA binding by condensin's HEAT-repeat subunits stimulates the SMC ATPase activity suggests a multistep mechanism for the loading of condensin onto chromosomes.
    Nature Structural & Molecular Biology 05/2014; 21(6). DOI:10.1038/nsmb.2831 · 13.31 Impact Factor
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    Sara Cuylen · Jutta Metz · Andrea Hruby · Christian H Haering ·
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    ABSTRACT: Successful segregation of chromosomes during mitosis and meiosis depends on the action of the ring-shaped condensin complex, but how condensin ensures the complete disjunction of sister chromatids is unknown. We show that the failure to segregate chromosome arms, which results from condensin release from chromosomes by proteolytic cleavage of its ring structure, leads to a DNA damage checkpoint-dependent cell-cycle arrest. Checkpoint activation is triggered by the formation of chromosome breaks during cytokinesis, which proceeds with normal timing despite the presence of lagging chromosome arms. Remarkably, enforcing condensin ring reclosure by chemically induced dimerization just before entry into anaphase is sufficient to restore chromosome arm segregation. We suggest that topological entrapment of chromosome arms by condensin rings ensures their clearance from the cleavage plane and thereby avoids their breakage during cytokinesis.
    Developmental Cell 11/2013; 27(4):469-78. DOI:10.1016/j.devcel.2013.10.018 · 9.71 Impact Factor
  • Ilaria Piazza · Christian H Haering · Anna Rutkowska ·
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    ABSTRACT: The successful transmission of complete genomes from mother to daughter cells during cell divisions requires the structural re-organization of chromosomes into individualized and compact structures that can be segregated by mitotic spindle microtubules. Multi-subunit protein complexes named condensins play a central part in this chromosome condensation process, but the mechanisms behind their actions are still poorly understood. An increasing body of evidence suggests that, in addition to their role in shaping mitotic chromosomes, condensin complexes have also important functions in directing the three-dimensional arrangement of chromatin fibers within the interphase nucleus. To fulfill their different functions in genome organization, the activity of condensin complexes and their localization on chromosomes need to be strictly controlled. In this review article, we outline the regulation of condensin function by phosphorylation and other posttranslational modifications at different stages of the cell cycle. We furthermore discuss how these regulatory mechanisms are used to control condensin binding to specific chromosome domains and present a comprehensive overview of condensin's interaction partners in these processes.
    Chromosoma 04/2013; 122(3). DOI:10.1007/s00412-013-0405-1 · 4.60 Impact Factor
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    Christian H Haering · Ana Losada ·
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    ABSTRACT: The 106th Boehringer Ingelheim Fonds International Titisee Conference, 'Reconstituting Chromatin: From Self-assembly to Self-organization', took place in October 2012. The organizers, Andrea Musacchio and Tom Muir, brought together biologists, chemists and physicists to discuss the principles of chromosome assembly and organization. Topics of discussion ranged from new insights gained from the static views provided by crystal structures to analyses of chromatin dynamics inside living cells.
    EMBO Reports 01/2013; 14(2). DOI:10.1038/embor.2012.221 · 9.06 Impact Factor
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    ABSTRACT: Chromosomes undergo extensive conformational rearrangements in preparation for their segregation during cell divisions. Insights into the molecular mechanisms behind this still poorly understood condensation process require the development of new approaches to quantitatively assess chromosome formation in vivo. In this study, we present a live-cell microscopy-based chromosome condensation assay in the fission yeast Schizosaccharomyces pombe. By automatically tracking the three-dimensional distance changes between fluorescently marked chromosome loci at high temporal and spatial resolution, we analyze chromosome condensation during mitosis and meiosis and deduct defined parameters to describe condensation dynamics. We demonstrate that this method can determine the contributions of condensin, topoisomerase II, and Aurora kinase to mitotic chromosome condensation. We furthermore show that the assay can identify proteins required for mitotic chromosome formation de novo by isolating mutants in condensin, DNA polymerase ε, and F-box DNA helicase I that are specifically defective in pro-/metaphase condensation. Thus, the chromosome condensation assay provides a direct and sensitive system for the discovery and characterization of components of the chromosome condensation machinery in a genetically tractable eukaryote.
    Molecular and Cellular Biology 12/2012; 33(5). DOI:10.1128/MCB.01400-12 · 4.78 Impact Factor
  • Christian H Haering · Rolf Jessberger ·
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    ABSTRACT: Cells use ring-like structured protein complexes for various tasks in DNA dynamics. The tripartite cohesin ring is particularly suited to determine chromosome architecture, for it is large and dynamic, may acquire different forms, and is involved in several distinct nuclear processes. This review focuses on cohesin's role in structuring chromosomes during mitotic and meiotic cell divisions and during interphase.
    Experimental Cell Research 03/2012; 318(12):1386-93. DOI:10.1016/j.yexcr.2012.03.016 · 3.25 Impact Factor
  • Anna Rutkowska · Christian H. Haering · Carsten Schultz ·
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    ABSTRACT: Ein neuer chemischer In-vivo-Verknüpfer: xCrAsH, ein dimeres Derivat der Bisarsenitverbindung FlAsH, ermöglicht die hochspezifische, kovalente Verknüpfung zweier Proteine, die je eine zwölf Aminosäuren lange Markierung tragen. Dieses induzierbare und (durch Zugabe von Dithiolen) reversible System kann für die Detektion und Manipulation von Protein-Protein-Wechselwirkungen in vitro und in lebenden Zellen verwendet werden (siehe Bild).
    Angewandte Chemie 12/2011; 123(52). DOI:10.1002/ange.201106404
  • Anna Rutkowska · Christian H Haering · Carsten Schultz ·
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    ABSTRACT: As you like it: xCrAsH, a dimeric derivative of the arsenical compound FlAsH, enables the highly specific, covalent cross-linking of two proteins containing a 12 amino acid peptide tag. This inducible and (by addition of dithiols) reversible system can be used to detect and manipulate protein-protein interactions both in vitro and in living cells (see picture).
    Angewandte Chemie International Edition 12/2011; 50(52):12655-8. DOI:10.1002/anie.201106404 · 11.26 Impact Factor
  • Boryana Petrova · Christian H Haering ·
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    ABSTRACT: How are condensin complexes, the major organizers of mitotic chromosomes, targeted to their DNA substrate? Recent discoveries suggest that a remarkable interplay between recruitment factors and kinase-regulated direct interactions with histone proteins enable condensin to structure chromatin fibers.
    ChemBioChem 11/2011; 12(16):2399-401. DOI:10.1002/cbic.201100531 · 3.09 Impact Factor
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    Sara Cuylen · Jutta Metz · Christian H Haering ·
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    ABSTRACT: The multisubunit condensin complex is essential for the structural organization of eukaryotic chromosomes during their segregation by the mitotic spindle, but the mechanistic basis for its function is not understood. To address how condensin binds to and structures chromosomes, we have isolated from Saccharomyces cerevisiae cells circular minichromosomes linked to condensin. We find that either linearization of minichromosome DNA or proteolytic opening of the ring-like structure formed through the connection of the two ATPase heads of condensin's structural maintenance of chromosomes (SMC) heterodimer by its kleisin subunit eliminates their association. This suggests that condensin rings encircle chromosomal DNA. We further show that release of condensin from chromosomes by ring opening in dividing cells compromises the partitioning of chromosome regions distal to centromeres. Condensin hence forms topological links within chromatid arms that provide the arms with the structural rigidity necessary for their segregation.
    Nature Structural & Molecular Biology 07/2011; 18(8):894-901. DOI:10.1038/nsmb.2087 · 13.31 Impact Factor
  • Sara Cuylen · Christian H Haering ·
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    ABSTRACT: The correct segregation of eukaryotic genomes requires the resolution of sister DNA molecules and their movement into opposite halves of the cell before cell division. The dynamic changes chromosomes need to undergo during these events depend on the action of a multi-subunit SMC (structural maintenance of chromosomes) protein complex named condensin, but its molecular function in chromosome segregation is still poorly understood. Recent studies suggest that condensin has a role in the removal of sister chromatid cohesin, in sister chromatid decatenation by topoisomerases, and in the structural reconfiguration of mitotic chromosomes. In this review we discuss possible mechanisms that could explain the variety of condensin actions during chromosome segregation.
    Trends in cell biology 07/2011; 21(9):552-9. DOI:10.1016/j.tcb.2011.06.003 · 12.01 Impact Factor
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    ABSTRACT: Cohesin's structural maintenance of chromosome 1 (Smc1) and Smc3 are rod-shaped proteins with 50-nm long intra-molecular coiled-coil arms with a heterodimerization domain at one end and an ABC-like nucleotide-binding domain (NBD) at the other. Heterodimerization creates V-shaped molecules with a hinge at their centre. Inter-connection of NBDs by Scc1 creates a tripartite ring within which, it is proposed, sister DNAs are entrapped. To investigate whether cohesin's hinge functions as a possible DNA entry gate, we solved the crystal structure of the hinge from Mus musculus, which like its bacterial counterpart is characterized by a pseudo symmetric heterodimeric torus containing a small channel that is positively charged. Mutations in yeast Smc1 and Smc3 that together neutralize the channel's charge have little effect on dimerization or association with chromosomes, but are nevertheless lethal. Our finding that neutralization reduces acetylation of Smc3, which normally occurs during replication and is essential for cohesion, suggests that the positively charged channel is involved in a major conformational change during S phase.
    The EMBO Journal 01/2011; 30(2):364-78. DOI:10.1038/emboj.2010.315 · 10.43 Impact Factor
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    Sara Cuylen · Christian H Haering ·
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    ABSTRACT: To control cell-type specific gene expression, transcription factors bound at distant enhancer sites need to come into the vicinity of promoters. In a recent Nature article, Kagey et al. (2010) provide evidence that Mediator and Cohesin protein complexes cooperate in the formation of enhancer-promoter DNA loops.
    Cell stem cell 10/2010; 7(4):424-6. DOI:10.1016/j.stem.2010.09.006 · 22.27 Impact Factor
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    Kim Nasmyth · Christian H Haering ·
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    ABSTRACT: The cohesin complex is a major constituent of interphase and mitotic chromosomes. Apart from its role in mediating sister chromatid cohesion, it is also important for DNA double-strand-break repair and transcriptional control. The functions of cohesin are regulated by phosphorylation, acetylation, ATP hydrolysis, and site-specific proteolysis. Recent evidence suggests that cohesin acts as a novel topological device that traps chromosomal DNA within a large tripartite ring formed by its core subunits.
    Annual Review of Genetics 08/2009; 43(1):525-58. DOI:10.1146/annurev-genet-102108-134233 · 15.72 Impact Factor
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    Christian H Haering ·

    Chromosome Research 02/2009; 17(2):127-9. DOI:10.1007/s10577-008-9008-8 · 2.48 Impact Factor
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    Christian H Haering · Ana-Maria Farcas · Prakash Arumugam · Jean Metson · Kim Nasmyth ·
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    ABSTRACT: Sister chromatid cohesion, which is essential for mitosis, is mediated by a multi-subunit protein complex called cohesin. Cohesin's Scc1, Smc1 and Smc3 subunits form a tripartite ring structure, and it has been proposed that cohesin holds sister DNA molecules together by trapping them inside its ring. To test this, we used site-specific crosslinking to create chemical connections at the three interfaces between the three constituent polypeptides of the ring, thereby creating covalently closed cohesin rings. As predicted by the ring entrapment model, this procedure produced dimeric DNA-cohesin structures that are resistant to protein denaturation. We conclude that cohesin rings concatenate individual sister minichromosome DNA molecules.
    Nature 08/2008; 454(7202):297-301. DOI:10.1038/nature07098 · 41.46 Impact Factor
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    Prakash Arumugam · Tatsuya Nishino · Christian H Haering · Stephan Gruber · Kim Nasmyth ·
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    ABSTRACT: Cohesin, a multisubunit protein complex conserved from yeast to humans, holds sister chromatids together from the onset of replication to their separation during anaphase. Cohesin consists of four core subunits, namely Smc1, Smc3, Scc1, and Scc3. Smc1 and Smc3 proteins are characterized by 50-nm-long anti-parallel coiled coils flanked by a globular hinge domain and an ABC-like ATPase head domain. Whereas Smc1 and Smc3 heterodimerize via their hinge domains, the kleisin subunit Scc1 connects their ATPase heads, and this results in the formation of a large ring. Biochemical studies suggest that cohesin might trap sister chromatids within its ring, and genetic evidence suggests that ATP hydrolysis is required for the stable association of cohesin with chromosomes. However, the precise role of the ATPase domains remains enigmatic. Characterization of cohesin's ATPase activity suggests that hydrolysis depends on the binding of ATP to both Smc1 and Smc3 heads. However, ATP hydrolysis at the two active sites is not per se cooperative. We show that the C-terminal winged-helix domain of Scc1 stimulates the ATPase activity of the Smc1/Smc3 heterodimer by promoting ATP binding to Smc1's head. In contrast, we do not detect any effect of Scc1's N-terminal domain on Smc1/Smc3 ATPase activity. Our studies reveal that Scc1 not only connects the Smc1 and Smc3 ATPase heads but also regulates their ATPase activity.
    Current Biology 11/2006; 16(20):1998-2008. DOI:10.1016/j.cub.2006.09.002 · 9.57 Impact Factor

Publication Stats

3k Citations
318.39 Total Impact Points


  • 2009-2015
    • European Molecular Biology Laboratory
      • Cell Biology and Biophysics Unit (Heidelberg)
      Heidelburg, Baden-Württemberg, Germany
  • 2006
    • University of Oxford
      • Department of Biochemistry
      Oxford, England, United Kingdom
  • 2002-2004
    • Research Institute of Molecular Pathology
      Wien, Vienna, Austria