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WIREs Dev Biol
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Etiology and pathogenesis of the cohesinopathies

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Cohesin is a chromosome‐associated protein complex that plays many important roles in chromosome function. Genetic screens in yeast originally identified cohesin as a key regulator of chromosome segregation. Subsequently, work by various groups has identified cohesin as critical for additional processes such as DNA damage repair, insulator function, gene regulation, and chromosome condensation. Mutations in the genes encoding cohesin and its accessory factors result in a group of developmental and intellectual impairment diseases termed ‘cohesinopathies.’ How mutations in cohesin genes cause disease is not well understood as precocious chromosome segregation is not a common feature in cells derived from patients with these syndromes. In this review, the latest findings concerning cohesin's function in the organization of chromosome structure and gene regulation are discussed. We propose that the cohesinopathies are caused by changes in gene expression that can negatively impact translation. The similarities and differences between cohesinopathies and ribosomopathies, diseases caused by defects in ribosome biogenesis, are discussed. The contribution of cohesin and its accessory proteins to gene expression programs that support translation suggests that cohesin provides a means of coupling chromosome structure with the translational output of cells. WIREs Dev Biol 2015, 4:489–504. doi: 10.1002/wdev.190 This article is categorized under: Gene Expression and Transcriptional Hierarchies > Gene Networks and Genomics Birth Defects > Craniofacial and Nervous System Anomalies
Schematic diagram of the cohesin complex. Cohesin is composed of four subunits. Smc1 and Smc3 (blue) are long polypeptides that form a hinge domain at one end and an ATPase domain at the other end by folding back on themselves to form antiparallel coiled‐coil interactions. The SMC heads are connected by the α‐kleisin RAD21 (green), which interacts with the fourth subunit, SA1 or SA2 (pink).
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Genome‐wide analysis of cohesin (SMC1) binding in the mouse genome. (a) SMC1 peaks were first defined and then a window ±1 kb on either side is shown for each factor. Clustering was performed as described for Figure . Cohesin peaks correlate well with CTCF binding. (b) Cohesin (SMC1) binds at more intergenic and intronic regions of genes than promoters. Gene ontology (GO) analysis of the active genes associated with cohesin in mESCs showed enrichment for genes involved in cell morphogenesis, cellular signal transduction, cellular developmental process, and cell adhesion.
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Analysis of the cohesin loader factor (NIPBL) binding throughout the genome of mouse embryonic stem cells. (a) NIPBL peaks from chromatin immunoprecipitation (ChIP) seq data were defined along with windows of ±1 kb on either side. These were then used to select the ChIP signal for each additional factor shown. ChIP‐seq data were subjected to unbiased clustering using seqMiner v1.3.3 package. Kmeans rank was used as the method of clustering, with the following parameters: left and right extensions = 1 kb; internal bins = 160; flanking region bins = 20; and the number of clusters = 7. NIPBL binds to active genes, enhancer regions, and intergenic and intronic regions of genes. NIPBL does not colocalize with CTCF. (b) The majority of NIPBL‐binding sites were at the promoter regions of genes. Gene ontology (GO) analysis of NIPBL‐bound active genes showed enrichment for genes important for RNA processing, mRNA processing, and RNA splicing.
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Schematic diagram depicting functions of cohesin at noncentromeric sites. (a) Double‐strand break (DSB) repair is facilitated by cohesin binding to the break site. Cohesion is also re‐enforced genome‐wide in response to a DSB. (b) Cohesin regulates gene expression by gene looping to promote long‐range (1) promoter–enhancer communication, (2) promoter–terminator interaction (middle), or (3) insulation. These types of events may contribute to chromatin organization within topological domains. (c) Cohesin promotes chromosome condensation.
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Schematic diagram showing cohesin regulation throughout the cell cycle. Cohesin (blue) is loaded onto chromosomes in telophase/G1 phase by the NIPBL–MAU2 heterodimer and requires the opening of the hinge domain of SMC1A and SMC3 for DNA entry. Cohesion establishment at S phase is facilitated by ESCO1/2‐dependent acetylation of the SMC3 head domain, making cohesin refractory to removal from chromatin by WAPL. Cohesion is then maintained by other proteins such as WAPL, PDS5, and Sororin. Cohesin can be removed in prophase in a separase‐independent manner from chromosome arms. This removal depends on PLK1 and WAPL/PDS5. Pericentromeric cohesion is protected by shugoshin and PP2A. At the onset of mitosis, pericentromeric cohesion is destroyed by proteolytic cleavage of RAD21 by separase and recycled for the next cell cycle. Recycling of the SMC3 subunit requires deacetylation by HDAC8.
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