Molecular Genetics of Cohesinopathies

Abstract

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.

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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. http://www.els.net [doi: 10.1002/9780470015902.a0025309]