Structural Insights into Ring Formation of Cohesin and Related Smc Complexes

Cohesin facilitates sister chromatid cohesion through the formation of a large ring structure that encircles DNA. Its function relies on two structural maintenance of chromosomes (Smc) proteins, which are found in almost all organisms tested, from bacteria to humans. In accordance with their ubiquity, Smc complexes, such as cohesin, condensin, Smc5-6, and the dosage compensation complex, affect almost all processes of DNA homeostasis. Although their precise molecular mechanism remains enigmatic, here we provide an overview of the architecture of eukaryotic Smc complexes with a particular focus on cohesin, which has seen the most progress recently. Given the evident conservation of many structural features between Smc complexes, it is expected that architecture and topology will have a significant role when deciphering their precise molecular mechanisms.

[1]  H. D. Ulrich,et al.  A Prokaryotic Condensin/Cohesin-Like Complex Can Actively Compact Chromosomes from a Single Position on the Nucleoid and Binds to DNA as a Ring-Like Structure , 2003, Molecular and Cellular Biology.

[2]  B. Meyer.  Targeting X chromosomes for repression. , 2010, Current opinion in genetics & development.

[3]  M. Lopes,et al.  Error-Free DNA Damage Tolerance and Sister Chromatid Proximity during DNA Replication Rely on the Polα/Primase/Ctf4 Complex , 2015, Molecular cell.

[4]  F. Uhlmann,et al.  DNA Entry into and Exit out of the Cohesin Ring by an Interlocking Gate Mechanism , 2015, Cell.

[5]  M. Heck,et al.  The evolution of ATPase activity in SMC proteins , 2006, Proteins.

[6]  J. Javerzat,et al.  Pds5 promotes cohesin acetylation and stable cohesin–chromosome interaction , 2012, EMBO reports.

[7]  Kim Nasmyth,et al.  Shugoshin Prevents Dissociation of Cohesin from Centromeres During Mitosis in Vertebrate Cells , 2005, PLoS biology.

[8]  Kim Nasmyth,et al.  Cleavage of Cohesin by the CD Clan Protease Separin Triggers Anaphase in Yeast , 2000, Cell.

[9]  John A. Tainer,et al.  Structural Biology of Rad50 ATPase ATP-Driven Conformational Control in DNA Double-Strand Break Repair and the ABC-ATPase Superfamily , 2000, Cell.

[10]  P. Rao,et al.  A handcuff model for the cohesin complex , 2008, The Journal of cell biology.

[11]  I. Krantz,et al.  Drosophila Nipped-B Mutants Model Cornelia de Lange Syndrome in Growth and Behavior , 2015, PLoS genetics.

[12]  L. Aragón,et al.  The unnamed complex: what do we know about Smc5-Smc6? , 2009, Chromosome Research.

[13]  Aki Minoda,et al.  Double-Strand Breaks in Heterochromatin Move Outside of a Dynamic HP1a Domain to Complete Recombinational Repair , 2011, Cell.

[14]  J. Peters,et al.  How cohesin and CTCF cooperate in regulating gene expression , 2009, Chromosome Research.

[15]  M. McKay,et al.  Conserved disruptions in the predicted coiled-coil domains of eukaryotic SMC complexes: implications for structure and function. , 2002, Genome research.

[16]  H. Aburatani,et al.  Cohesin mediates transcriptional insulation by CCCTC-binding factor , 2008, Nature.

[17]  B. Oh,et al.  An asymmetric SMC–kleisin bridge in prokaryotic condensin , 2013, Nature Structural &Molecular Biology.

[18]  J. Löwe,et al.  Crystal structure of the SMC head domain: an ABC ATPase with 900 residues antiparallel coiled-coil inserted. , 2001, Journal of molecular biology.

[19]  David A. Orlando,et al.  Mediator and Cohesin Connect Gene Expression and Chromatin Architecture , 2010, Nature.

[20]  K. Nasmyth,et al.  Evidence that Loading of Cohesin Onto Chromosomes Involves Opening of Its SMC Hinge , 2006, Cell.

[21]  K Nasmyth,et al.  Cohesin's binding to chromosomes depends on a separate complex consisting of Scc2 and Scc4 proteins. , 2000, Molecular cell.

[22]  K. Nasmyth,et al.  Rec8-containing cohesin maintains bivalents without turnover during the growing phase of mouse oocytes. , 2010, Genes & development.

[23]  R. Nicklas.  How Cells Get the Right Chromosomes , 1997, Science.

[24]  W. G. Kelly,et al.  Regulation of the X chromosomes in Caenorhabditis elegans. , 2014, Cold Spring Harbor perspectives in biology.

[25]  W. Earnshaw,et al.  Condensin: Architect of mitotic chromosomes , 2009, Chromosome Research.

[26]  D. Schatz,et al.  A role for cohesin in T cell receptor rearrangement and thymocyte differentiation , 2011, Nature.

[27]  C. Haering,et al.  Condensin structures chromosomal DNA through topological links , 2011, Nature Structural &Molecular Biology.

[28]  J. Peters,et al.  Wapl Controls the Dynamic Association of Cohesin with Chromatin , 2006, Cell.

[29]  J. Ellenberg,et al.  Live-Cell Imaging Reveals a Stable Cohesin-Chromatin Interaction after but Not before DNA Replication , 2006, Current Biology.

[30]  I. Krantz,et al.  Mutation Spectrum and Genotype–Phenotype Correlation in Cornelia de Lange Syndrome , 2013, Human mutation.

[31]  T. Hirano,et al.  Human Wapl Is a Cohesin-Binding Protein that Promotes Sister-Chromatid Resolution in Mitotic Prophase , 2006, Current Biology.

[32]  Z. Otwinowski,et al.  Structure of the human cohesin inhibitor Wapl , 2013, Proceedings of the National Academy of Sciences.

[33]  Karl Mechtler,et al.  Eco1 Is a Novel Acetyltransferase that Can Acetylate Proteins Involved in Cohesion , 2002, Current Biology.

[34]  B. Oh,et al.  SMC condensin entraps chromosomal DNA by an ATP hydrolysis dependent loading mechanism in Bacillus subtilis , 2015, eLife.

[35]  C. Morrison,et al.  Roles of Vertebrate Smc5 in Sister Chromatid Cohesion and Homologous Recombinational Repair , 2011, Molecular and Cellular Biology.

[36]  K. Nasmyth,et al.  Cohesin ensures bipolar attachment of microtubules to sister centromeres and resists their precocious separation , 2000, Nature Cell Biology.

[37]  Thomas Whitington,et al.  Transcription Factor Binding in Human Cells Occurs in Dense Clusters Formed around Cohesin Anchor Sites , 2013, Cell.

[38]  K. Kimura,et al.  ATP-Dependent Positive Supercoiling of DNA by 13S Condensin: A Biochemical Implication for Chromosome Condensation , 1997, Cell.

[39]  Steven P. Gygi,et al.  A Molecular Determinant for the Establishment of Sister Chromatid Cohesion , 2008, Science.

[40]  Neus Colomina,et al.  The Smc5/6 complex is required for dissolution of DNA-mediated sister chromatid linkages , 2010, Nucleic acids research.

[41]  H. Lecar,et al.  ATP‐dependent bacterial transporters and cystic fibrosis: analogy between channels and transporters , 1992, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[42]  Juri Rappsilber,et al.  Cohesin-Dependent Association of Scc2/4 with the Centromere Initiates Pericentromeric Cohesion Establishment , 2013, Current Biology.

[43]  Nenggang Zhang,et al.  Handcuff for sisters: A new model for sister chromatid cohesion , 2009, Cell cycle.

[44]  K. Nasmyth,et al.  Condensin confers the longitudinal rigidity of chromosomes , 2015, Nature Cell Biology.

[45]  Boris Lenhard,et al.  A Cohesin-Independent Role for NIPBL at Promoters Provides Insights in CdLS , 2014, PLoS genetics.

[46]  Alastair Kerr,et al.  Structural evidence for Scc4-dependent localization of cohesin loading , 2015, eLife.

[47]  K. Shirahige,et al.  Postreplicative Formation of Cohesion Is Required for Repair and Induced by a Single DNA Break , 2007, Science.

[48]  G. Witte,et al.  Structure and DNA binding activity of the mouse condensin hinge domain highlight common and diverse features of SMC proteins , 2010, Nucleic acids research.

[49]  Ruedi Aebersold,et al.  Characterization of a DNA exit gate in the human cohesin ring , 2014, Science.

[50]  A. Lehmann.  The role of SMC proteins in the responses to DNA damage. , 2005, DNA repair.

[51]  M. Singleton,et al.  Structural insights into the regulation of cohesion establishment by Wpl1 , 2013, The EMBO journal.

[52]  Tim Hunt,et al.  Cut2 proteolysis required for sister-chromatid separation in fission yeast , 1996, Nature.

[53]  D. Dorsett,et al.  Cohesin Selectively Binds and Regulates Genes with Paused RNA Polymerase , 2011, Current Biology.

[54]  J. Berger,et al.  The crystal structure of the hinge domain of the Escherichia coli structural maintenance of chromosomes protein MukB. , 2010, Journal of molecular biology.

[55]  Frank Eisenhaber,et al.  Pds5 cooperates with cohesin in maintaining sister chromatid cohesion , 2000, Current Biology.

[56]  Jürgen Cox,et al.  Proteomics reveals dynamic assembly of repair complexes during bypass of DNA cross-links , 2015, Science.

[57]  D. Dorsett.  Cohesin: genomic insights into controlling gene transcription and development. , 2011, Current opinion in genetics & development.

[58]  Q. Qu,et al.  Structure of cohesin subcomplex pinpoints direct shugoshin–Wapl antagonism in centromeric cohesion , 2014, Nature Structural &Molecular Biology.

[59]  J. Peters,et al.  Two Distinct Pathways Remove Mammalian Cohesin from Chromosome Arms in Prophase and from Centromeres in Anaphase , 2000, Cell.

[60]  S. Hadjur,et al.  Genetic Tailors: CTCF and Cohesin Shape the Genome During Evolution. , 2015, Trends in genetics : TIG.

[61]  A. Losada,et al.  Cohesin in cancer: chromosome segregation and beyond , 2014, Nature Reviews Cancer.

[62]  R. Kobayashi,et al.  Condensins, Chromosome Condensation Protein Complexes Containing XCAP-C, XCAP-E and a Xenopus Homolog of the Drosophila Barren Protein , 1997, Cell.

[63]  J. Walker,et al.  Distantly related sequences in the alpha‐ and beta‐subunits of ATP synthase, myosin, kinases and other ATP‐requiring enzymes and a common nucleotide binding fold. , 1982, The EMBO journal.

[64]  Niko Välimäki,et al.  CTCF/cohesin-binding sites are frequently mutated in cancer , 2015, Nature Genetics.

[65]  A. Losada,et al.  Pds5B is required for cohesion establishment and Aurora B accumulation at centromeres , 2013, The EMBO journal.

[66]  T. Hirano,et al.  Releasing cohesin from chromosome arms in early mitosis: opposing actions of Wapl-Pds5 and Sgo1. , 2009, Genes & development.

[67]  F. Uhlmann,et al.  Biochemical reconstitution of topological DNA binding by the cohesin ring , 2013, Nature.

[68]  Kim Nasmyth,et al.  Closing the cohesin ring: Structure and function of its Smc3-kleisin interface , 2014, Science.

[69]  D. Sherratt,et al.  The bacterial chromosome: architecture and action of bacterial SMC and SMC-like complexes , 2013, FEMS microbiology reviews.

[70]  Karl Mechtler,et al.  Protein phosphatase 2A protects centromeric sister chromatid cohesion during meiosis I , 2006, Nature.

[71]  K. Nasmyth.  Cohesin: a catenase with separate entry and exit gates? , 2011, Nature Cell Biology.

[72]  P. Nurse,et al.  Cohesin Rec8 is required for reductional chromosome segregation at meiosis , 1999, Nature.

[73]  Maojun Yang,et al.  MAGE-RING protein complexes comprise a family of E3 ubiquitin ligases. , 2010, Molecular cell.

[74]  C. Dekker,et al.  Condensin Smc2-Smc4 Dimers Are Flexible and Dynamic , 2016, Cell reports.

[75]  K. Nasmyth,et al.  ATP Hydrolysis Is Required for Relocating Cohesin from Sites Occupied by Its Scc2/4 Loading Complex , 2011, Current Biology.

[76]  J. Ellenberg,et al.  Wapl is an essential regulator of chromatin structure and chromosome segregation , 2013, Nature.

[77]  Kim Nasmyth,et al.  Structure and stability of cohesin's Smc1-kleisin interaction. , 2004, Molecular cell.

[78]  J. Söding,et al.  The Mre11:Rad50 Structure Shows an ATP-Dependent Molecular Clamp in DNA Double-Strand Break Repair , 2011, Cell.

[79]  I. Sumara,et al.  Characterization of Vertebrate Cohesin Complexes and Their Regulation in Prophase , 2000, The Journal of cell biology.

[80]  T. Hirano,et al.  Reconstitution of mitotic chromatids with a minimum set of purified factors , 2015, Nature Cell Biology.

[81]  M. Singleton,et al.  Structural Studies Reveal the Functional Modularity of the Scc2-Scc4 Cohesin Loader. , 2015, Cell reports.

[82]  J. Peters,et al.  Cohesin Cleavage by Separase Required for Anaphase and Cytokinesis in Human Cells , 2001, Science.

[83]  Sebastian Maurer-Stroh,et al.  Kleisins: a superfamily of bacterial and eukaryotic SMC protein partners. , 2003, Molecular cell.

[84]  Kim Nasmyth,et al.  Molecular architecture of SMC proteins and the yeast cohesin complex. , 2002, Molecular cell.

[85]  K. Nasmyth,et al.  Crystal Structure of the Cohesin Gatekeeper Pds5 and in Complex with Kleisin Scc1 , 2016, Cell reports.

[86]  E. Watrin,et al.  Gene regulation and chromatin organization: relevance of cohesin mutations to human disease. , 2016, Current opinion in genetics & development.

[87]  K. Nasmyth,et al.  A positively charged channel within the Smc1/Smc3 hinge required for sister chromatid cohesion , 2010, The EMBO journal.

[88]  A. Varshavsky,et al.  Terminal stages of SV40 DNA replication proceed via multiply intertwined catenated dimers , 1980, Cell.

[89]  Margarete M S Heck,et al.  The evolution of SMC proteins: phylogenetic analysis and structural implications. , 2004, Molecular biology and evolution.

[90]  Yan Li,et al.  Structure of the Pds5-Scc1 Complex and Implications for Cohesin Function. , 2016, Cell reports.

[91]  Ilan Davis,et al.  Cohesin cleavage and Cdk inhibition trigger formation of daughter nuclei , 2010, Nature Cell Biology.

[92]  H. Erickson,et al.  Condensin and cohesin display different arm conformations with characteristic hinge angles , 2002, The Journal of cell biology.

[93]  Nicklas Rb.  How Cells Get the Right Chromosomes , 1997, Science.

[94]  K. Shirahige,et al.  Smc5/6-mediated regulation of replication progression contributes to chromosome assembly during mitosis in human cells , 2014, Molecular biology of the cell.

[95]  J. Palecek,et al.  Kite Proteins: a Superfamily of SMC/Kleisin Partners Conserved Across Bacteria, Archaea, and Eukaryotes. , 2015, Structure.

[96]  H. Fuchs,et al.  SMC6 is an essential gene in mice, but a hypomorphic mutant in the ATPase domain has a mild phenotype with a range of subtle abnormalities. , 2013, DNA repair.

[97]  K. Shirahige,et al.  During Replication Stress, Non-Smc Element 5 (Nse5) Is Required for Smc5/6 Protein Complex Functionality at Stalled Forks* , 2012, The Journal of Biological Chemistry.

[98]  Job Dekker,et al.  Condensin promotes the juxtaposition of DNA flanking its loading site in Bacillus subtilis , 2015, Genes & development.

[99]  D. Koshland,et al.  DNA Double-Strand Breaks Trigger Genome-Wide Sister-Chromatid Cohesion Through Eco1 (Ctf7) , 2007, Science.

[100]  K. Nasmyth,et al.  Cohesin’s DNA Exit Gate Is Distinct from Its Entrance Gate and Is Regulated by Acetylation , 2012, Cell.

[101]  F. Uhlmann,et al.  Budding Yeast Wapl Controls Sister Chromatid Cohesion Maintenance and Chromosome Condensation , 2013, Current Biology.

[102]  K. Nasmyth,et al.  Pds5 promotes and protects cohesin acetylation , 2013, Proceedings of the National Academy of Sciences.

[103]  Nam Ki Lee,et al.  Molecular Basis for SMC Rod Formation and Its Dissolution upon DNA Binding , 2015, Molecular cell.

[104]  P. Russell,et al.  ABC ATPase signature helices in Rad50 link nucleotide state to Mre11 interface for DNA repair , 2012, Nature Structural &Molecular Biology.

[105]  K. Nasmyth,et al.  A physical assay for sister chromatid cohesion in vitro. , 2007, Molecular cell.

[106]  O. Stemmann,et al.  Prophase pathway‐dependent removal of cohesin from human chromosomes requires opening of the Smc3–Scc1 gate , 2013, The EMBO journal.

[107]  Philip East,et al.  Eco1-Dependent Cohesin Acetylation During Establishment of Sister Chromatid Cohesion , 2008, Science.

[108]  Xiaolan Zhao,et al.  A SUMO ligase is part of a nuclear multiprotein complex that affects DNA repair and chromosomal organization. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[109]  M. Bermudez-lopez,et al.  A SUMO-Dependent Step during Establishment of Sister Chromatid Cohesion , 2012, Current Biology.

[110]  O. Cohen-Fix,et al.  Chromosome cohesion: ring around the sisters? , 2002, Trends in biochemical sciences.

[111]  Yunje Cho,et al.  Crystal structure of the Mre11-Rad50-ATPγS complex: understanding the interplay between Mre11 and Rad50. , 2011, Genes & development.

[112]  C. Haering,et al.  Shaping mitotic chromosomes: From classical concepts to molecular mechanisms , 2015, BioEssays : news and reviews in molecular, cellular and developmental biology.

[113]  V. Guacci,et al.  Pds5p Is an Essential Chromosomal Protein Required for Both Sister Chromatid Cohesion and Condensation in Saccharomyces cerevisiae , 2000, The Journal of cell biology.

[114]  T. Hirano.  Condensins: universal organizers of chromosomes with diverse functions. , 2012, Genes & development.

[115]  K. Shirahige,et al.  The maintenance of chromosome structure: positioning and functioning of SMC complexes , 2014, Nature Reviews Molecular Cell Biology.

[116]  Karl Mechtler,et al.  Building sister chromatid cohesion: smc3 acetylation counteracts an antiestablishment activity. , 2009, Molecular cell.

[117]  Tohru Natsume,et al.  Shugoshin collaborates with protein phosphatase 2A to protect cohesin , 2006, Nature.

[118]  K. Nasmyth,et al.  Structure and function of cohesin’s Scc3/SA regulatory subunit , 2014, FEBS letters.

[119]  Karl Mechtler,et al.  Dissociation of Cohesin from Chromosome Arms and Loss of Arm Cohesion during Early Mitosis Depends on Phosphorylation of SA2 , 2005, PLoS biology.