Molecular Genetics of Cohesinopathies


Maintenance of sister chromatid cohesion (SCC) until anaphase during cell division is essential for a correct repartition of genetic material to daughter cells. In the search for molecules involved in this process, two independent laboratories have characterised a protein complex, which was denominated the cohesin complex. Although, in the early years, the research focus was on its role in SCC, some years later, new findings have shown that the cohesin complex is involved in several crucial processes in the genome dynamic, deoxyribonucleic acid (DNA)‐repair, DNA replication and control of transcription and gene expression. The metabolism of cohesin complex and its chromosome interactions are regulated by other proteins, which have been referred as cohesin cofactors or cohesin regulators. Mutations in the cohesin subunits and cohesin cofactor genes, which show a little or no effect in chromosome cohesion, but influence significantly changes in the gene expression, provoke some human pathologies that we know as cohesinopathies.

Key Concepts:

  • The protein complex was given the name ‘cohesin’ because it was first characterised in sister chromatid cohesion during chromosome segregation.

  • Cohesin complex function during cell division is essential for correct chromosome segregation to daughter cells and to avoid aneuploidies and tumour formation.

  • Cohesin complex have other important functions apart from chromosome segregation in the genome dynamic, such us DNA‐damage repair, DNA duplication and gene expression control.

  • The role of cohesin complex in gene expression control is essential for right organism development.

  • Cohesin complex functions are also regulated by the cohesin‐interacting proteins named cohesin cofactors or cohesin regulators.

  • Mutations in the genes codifying for cohesin complex subunits and/or cohesin cofactors provoke human syndromes denominated cohesinopathies.

Keywords: cohesin; cohesinopathies; Cornelia de Lange syndrome; Roberts syndrome; transcription control

Figure 1.

Cohesin complex. (a) Cohesin subunits: SMC1, SMC3 contain ATPase coiled‐coil and hinge domains; the kleisin subunit SCC1 and the HEAT domain subunit STAG. The subunits SMC1 β, RAD21L, REC8 and STAG3 (in red) are meiosis‐specific cohesins. (b) Ring model of cohesin complex in which a heterodimer of SMC1 and SMC3 subunits form a ring structure maintained also by interactions with the non‐SMC subunits SCC1/RAD21 and SCC3/STAG.

Figure 2.

Cohesin complex and cohesion regulatory factors. (a) Regulation of cohesin complex/chromatin association. The adherin/kollerin complex formed by SCC2/NIPBL and SCC4/MAU2 is essential for cohesin complex loading. The proteins PDS5, WAPL and the acetyltransferase ESCO2 are required for the establishment of cohesive function. ESCO2 acetylates the cohesin subunit SMC3. The protein called sororin interacts with the cohesin complex to maintain the cohesion. (b) Removing cohesin complex from chromatin. At the onset of mitosis, most of the cohesin complexes dissociate from chromatin by a mechanism that requires cohesin phosphorylation by different kinases and the participation of PDS5‐WAPL complex. A fraction of cohesin remains bound, essentially to the pericentromeric regions and is protected from removing by Shugoshin‐PP2A (protein phosphatase 2A). At the onset of anaphase, activation of the anaphase‐promoting complex APC/C drives the degradation of securin, an inhibitor of the protease, separase. Therefore, separase is activated and it can cleave the α‐kleisin subunit of the cohesin complex and dissolving centromeric cohesion.

Figure 3.

Cohesin and cohesin cofactors mutated in cohesinopathies. (a) In Cornelia de Lange disease, mutations in five human genes have been identified: three codifying for cohesin subunits, SMC1 α, SMC3 and RAD21, and two for cohesin regulators, NIPBL and HDAC8. (b) To date, only mutations in one gene, ESCO2 encoding for acetyltransferase, which acetylates two lysine residues of SMC3, have been involved in Roberts syndrome. * Human genes that have been identified with mutations in cohesinopathies.

Figure 4.

Cohesin complex in loop‐forming chromatin structures controlling gene expression. (1) The repression of transcription function of cohesin complex is mediated by interaction with chromatin‐bound CTCF insulator factor, preventing the interaction between gene 1 promoter and regulatory elements. (2) Chromatin loop structure formed by the interaction of mediator and/or other transcription coactivators with the cohesin complex allows enhancer–promoter interactions promoting gene 2 transcription.



Barbero JL (2009) Cohesins: chromatin architects in chromosome segregation, control of gene expression and much more. Cellular and Molecular Life Sciences 13: 2025–2035.

Barbero JL (2011) Cohesins and cohesin‐regulators: role in chromosome segregation/repair and potential in tumorigenesis. Atlas of Genetics and Cytogenetics in Oncology and Haematology. (accessed on September 2011).

Bose T, Lee KK, Lu S et al. (2012) Cohesin proteins promote ribosomal RNA production and protein translation in yeast and human cells. PLoS Genetics 8(6): e1002749.

Calvente A and Barbero JL (2012) Cohesins and cohesin‐regulators in meiosis. In: Swan A (ed.) Meiosis – Molecular Mechanisms and Cytogenetic Diversity, Rijeka, Croatia: InTech. pp. 35–66. ISBN: 978‐953‐51‐0118‐5.

Carramolino L, Lee BC, Zaballos A et al. (1997) DSA‐1, a nuclear protein encoded by one member of a novel gene family: molecular cloning and detection in hemopoietic organs. Gene 195: 151–159.

Chan KL, Roig MB, Hu B et al. (2012) Cohesin's DNA exit gate is distinct from its entrance gate and is regulated by acetylation. Cell 150: 961–974.

Deardorff MA, Bando M, Nakato R et al. (2012b) HDAC8 mutations in Cornelia de Lange syndrome affect the cohesin acetylation cycle. Nature 489: 313–317.

Deardorff MA, Kaur M, Yaeger D et al. (2007) Mutations in cohesin complex members SMC3 and SMC1A cause a mild variant of Cornelia de Lange syndrome with predominant mental retardation. American Journal of Human Genetics 80: 485–494.

Deardorff MA, Wilde JJ, Albrecht M et al. (2012a) RAD21 mutations cause a human cohesinopathy. American Journal of Human Genetics 90: 1014–1027.

Degner SC, Wong TP, Jankevicius G and Feeney AJ (2009) Cutting edge: developmental stage‐specific recruitment of cohesin to CTCF sites throughout immunoglobulin loci during B lymphocyte development. Journal of Immunology 182: 44–48.

Dorsett D (2004) Adherin: key to the cohesin ring and cornelia de Lange syndrome. Current Biology 14: 834–836.

Feeney AJ and Verma‐Gaur J (2012) CTCF‐cohesin complex: architect of chromatin structure regulates V(D)J rearrangement. Cell Research 22: 280–282.

Gordillo M, Vega H, Trainer AH et al. (2008) The molecular mechanism underlying Roberts syndrome involves loss of ESCO2 acetyltransferase activity. Human Molecular Genetics 17: 2172–2180.

Holwerda S and de Laat W (2012) Chromatin loops, gene positioning, and gene expression. Frontiers in Genetics 3: 217.

Horsfield JA, Anagnostou SH, Hu JK et al. (2007) Cohesin‐dependent regulation of Runx genes. Development 134: 2639–2649.

Hou F and Zou H (2005) Two human orthologues of Eco1/Ctf7 acetyltransferases are both required for proper sister‐chromatid cohesion. Molecular Biology of the Cell 16: 3908–3918.

Kagey MH, Newman JJ, Bilodeau S et al. (2010) Mediator and cohesin connect gene expression and chromatin architecture. Nature 467: 430–435.

Krantz ID, McCallum J, DeScipio C et al. (2004) Cornelia de Lange syndrome is caused by mutations in NIPBL, the human homolog of Drosophila melanogaster Nipped‐B. Nature Genetics 36: 631–635.

Lara‐Pezzi E, Pezzi N, Prieto I et al. (2004) Evidence of a transcriptional co‐activator function of cohesin STAG/SA/Scc3. Journal of Biological Chemistry 279: 6553–6559.

Losada A, Yokochi T and Hirano T (2005) Functional contribution of Pds5 to cohesin‐mediated cohesion in human cells and Xenopus egg extracts. Journal of Cell Science 118: 2133–2141.

Losada A, Yokochi T, Kobayashi R and Hirano T (2000) Identification and characterization of SA/Scc3 subunits in the Xenopus and human cohesin complexes. Journal of Cell Biology 150: 405–416.

Mannini L, Cucco F, Quarantotti V, Krantz ID and Musio A (2013) Mutation spectrum and genotype–phenotype correlation in Cornelia de Lange syndrome. Human Mutation 34: 1589–1596. doi:10.1002/humu.22430.

Merkenschlager M and Odom DT (2013) CTCF and cohesin: linking gene regulatory elements with their targets. Cell 152: 1285–1297.

Mishiro T, Ishihara K, Hino S et al. (2009) Architectural roles of multiple chromatin insulators at the human apolipoprotein gene cluster. EMBO Journal 28: 1234–1245.

Misulovin Z, Schwartz YB, Li XY et al. (2008) Association of cohesin and Nipped‐B with transcriptionally active regions of the Drosophila melanogaster genome. Chromosoma 117: 89–102.

Musio A, Selicorni A, Focarelli ML et al. (2006) X‐linked Cornelia de Lange syndrome owing to SMC1L1 mutations. Nature Genetics 38: 528–530.

Nasmyth K and Haering CH (2005) The structure and function of SMC and kleisin complexes. Annual Review of Biochemistry 74: 595–648.

Nishiyama T, Sykora MM, Huis In 't Veld PJ, Mechtler K and Peters JM, (2013) Aurora B and Cdk1 mediate Wapl activation and release of acetylated cohesin from chromosomes by phosphorylating Sororin. Proceedings of the National Academy of Sciences of the USA 110: 13404–13409.

Oliver C, Bedeschi MF, Blagowidow N et al. (2010) Cornelia de Lange syndrome: extending the physical and psychological phenotype. American Journal of Medical Genetics 152A: 1127–1135.

Parelho V, Hadjur S, Spivakov M et al. (2008) Cohesins functionally associate with CTCF on mammalian chromosome arms. Cell 132: 422–433.

Pauli A, Althoff F, Oliveira RA et al. (2008) Cell‐type‐specific TEV protease cleavage reveals cohesin functions in Drosophila neurons. Developmental Cell 14: 239–251.

Rankin S, Ayad NG and Kirschner MW (2005) Sororin, a substrate of the anaphase‐promoting complex, is required for sister chromatid cohesion in vertebrates. Molecular Cell 18: 185–200.

Remeseiro S, Cuadrado A, Gómez‐López G, Pisano DG and Losada A (2012) A unique role of cohesin‐SA1 in gene regulation and development. EMBO Journal 31: 2090–2102.

Remeseiro S, Cuadrado A, Kawauchi S et al. (2013) Reduction of Nipbl impairs cohesin loading locally and affects transcription but not cohesion‐dependent functions in a mouse model of Cornelia de Lange Syndrome. Biochimica et Biophysica Acta 1832: 2097–2102.

Revenkova E, Focarelli ML, Susani L et al. (2009) Cornelia de Lange syndrome mutations in SMC1A or SMC3 affect binding to DNA. Human Molecular Genetics 18: 418–427.

Rollins RA, Korom M, Aulner N, Martens A and Dorsett D (2004) Drosophila nipped‐B protein supports sister chromatid cohesion and opposes the stromalin/Scc3 cohesion factor to facilitate long‐range activation of the cut gene. Molecular Cell Biology 24: 3100–3111.

Rollins RA, Morcillo P and Dorsett D (1999) Nipped‐B, a Drosophila homologue of chromosomal adherins, participates in activation by remote enhancers in the cut and Ultrabithorax genes. Genetics 152: 577–593.

Rubio ED, Reiss DJ, Welcsh PL et al. (2008) CTCF physically links cohesin to chromatin. Proceedings of the National Academy of Sciences of the USA 105: 8309–8314.

Schaaf CA, Misulovin Z, Gause M et al. (2013a) Cohesin and polycomb proteins functionally interact to control transcription at silenced and active genes. PLoS Genetics 9: e1003560.

Schaaf CA, Misulovin Z, Gause M, Koenig A and Dorsett D (2013b) The Drosophila enhancer of split gene complex: Architecture and Coordinate Regulation by Notch, Cohesin and Polycomb Group Protein. G3 (Bethesda) 3: 1785–1794. doi: 10.1534/g3.113.007534.

Schuldiner O, Berdnik D, Levy JM et al. (2008) piggyBac‐based mosaic screen identifies a postmitotic function for cohesin in regulating developmental axon pruning. Developmental Cell 14: 227–238.

Shintomi K and Hirano T (2010) Sister chromatid resolution: a cohesin releasing network and beyond. Chromosoma 119: 459–467.

Slavin TP, Kuruvilla K, Curtis CA, Christ LA and Mitchell AL (2011) Isolated skeletal malformations in a child with a small mosaic ring microduplication of 18 p11.21q11.2: genotype–phenotype correlations. American Journal of Medical Genetics 155A: 618–621.

Stedman W, Kang H, Lin S et al. (2008) Cohesins localize with CTCF at the KSHV latency control region and at cellular c‐myc and H19/Igf2 insulators. EMBO Journal 27: 654–666.

Strübbe G, Popp C, Schmidt A et al. (2011) Polycomb purification by in vivo biotinylation tagging reveals cohesin and Trithorax group proteins as interaction partners. Proceedings of the National Academy of Sciences of the USA 108: 5572–5577.

Suja JA and Barbero JL (2009) Cohesin complexes and sister chromatid cohesion in mammalian meiosis. Genome Dynamics 5: 94–116.

Sumara I, Vorlaufer E, Gieffers C, Peters BH and Peters JM (2000) Characterization of vertebrate cohesin complexes and their regulation in prophase. Journal of Cell Biology 151: 749–762.

Taatjes DJ (2010) The human mediator complex: a versatile, genome‐wide regulator of transcription. Trends in Biochemical Sciences 35: 315–322.

Tonkin ET, Wang TJ, Lisgo S, Bamshad MJ and Strachan T (2004) NIPBL, encoding a homolog of fungal Scc2‐type sister chromatid cohesion proteins and fly Nipped‐B, is mutated in Cornelia de Lange syndrome. Nature Genetics 36: 636–641.

Vega H, Waisfisz Q, Gordillo M et al. (2005) Roberts syndrome is caused by mutations in ESCO2, a human homolog of yeast ECO1 that is essential for the establishment of sister chromatid cohesion. Nature Genetics 37: 468–470.

Wendt KS, Yoshida K, Itoh T et al. (2008) Cohesin mediates transcriptional insulation by CCCTC‐binding factor. Nature 451: 796–801.

Xu B, Lee KK, Zhang L and Gerton JL (2013) Stimulation of mTORC1 with L‐leucine rescues defects associated with Roberts syndrome. PLoS Genetics 9(10): e1003857.

Xu Z, Cetin B, Anger M et al. (2009) Structure and function of the PP2A‐shugoshin interaction. Molecules and Cells 35: 426–441.

Xu H, Tomaszewski JM and McKay MJ (2011) Can corruption of chromosome cohesion create a conduit to cancer? Nature Reviews Cancer 11: 199–210.

Yoshida K, Toki T, Okuno Y et al. (2013) The landscape of somatic mutations in Down syndrome‐related myeloid disorders. Nature Genetics 45: 1293–1299. doi: 10.1038/ng.2759.

Zhang B, Chang J, Fu M et al. (2009) Dosage effects of cohesin regulatory factor PDS5 on mammalian development: implications for cohesinopathies. PLoS One 4: e5232.

Zhang B, Jain S, Song H et al. (2007) Mice lacking sister chromatid cohesion protein PDS5B exhibit developmental abnormalities reminiscent of Cornelia de Lange syndrome. Development 134: 3191–3201.

Further Reading

Ball AR Jr, Chen YY and Yokomori K (in press) Mechanisms of cohesin‐mediated gene regulation and lessons learned from cohesinopathies. Biochimica et Biophysica Acta pii: S1874‐9399(13)00160‐0. doi: 10.1016/j.bbagrm.2013.11.002.

Barbero JL (2011) Sister chromatid cohesion control and aneuploidy. Cytogenetic and Genome Research 133: 223–233.

Bose T and Gerton JL (2010) Cohesinopathies, gene expression, and chromatin organization. Journal of Cell Biology 189: 201–210.

Liu J and Krantz ID (2008) Cohesin and human disease. Annual Review of Genetics 9: 303–320.

Mehta GD, Kumar R, Srivastava S and Ghosh SK (2013) Cohesin: functions beyond sister chromatid cohesion. FEBS Letters 587: 2299–2312.

McNairn AJ and Gerton JL (2008) Cohesinopathies: one ring, many obligations. Mutation Research 647: 103–111.

Remeseiro S and Losada A (2013) Cohesin, a chromatin engagement ring. Current Opinion in Cell Biology 25: 63–71.

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Barbero, José L(Mar 2014) Molecular Genetics of Cohesinopathies. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0025309]