Cohesin

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Diagram of cohesin showing its four constituent protein subunits Cohesin.svg
Diagram of cohesin showing its four constituent protein subunits

Cohesin is a protein complex that mediates sister chromatid cohesion, homologous recombination, and DNA looping. Cohesin is formed of SMC3, SMC1, SCC1 and SCC3 (SA1 or SA2 in humans). Cohesin holds sister chromatids together after DNA replication until anaphase when removal of cohesin leads to separation of sister chromatids. The complex forms a ring-like structure and it is believed that sister chromatids are held together by entrapment inside the cohesin ring. Cohesin is a member of the SMC family of protein complexes which includes Condensin, MukBEF and SMC-ScpAB.

Contents

Cohesin was separately discovered in budding yeast ( Saccharomyces cerevisiae ) both by Douglas Koshland [1] and Kim Nasmyth in 1997. [2]

Structure

Models of SMC and cohesin structure Models of SMC and cohesin structure.svg
Models of SMC and cohesin structure

Cohesin is a multi-subunit protein complex, made up of SMC1, SMC3, RAD21 and SCC3 (SA1 or SA2). [3] SMC1 and SMC3 are members of the Structural Maintenance of Chromosomes (SMC) family. SMC proteins have two main structural characteristics: an ATP-binding cassette-like 'head' domain with ATPase activity (formed by the interaction of the N- and C- terminals) and a hinge domain that allows dimerization of SMCs. The head and the hinge domains are connected to each other via long anti-parallel coiled coils. The dimer is present in a V-shaped form, connected by the hinges.

The N-terminal domain of RAD21 contains two α-helices which forms a three helix bundle with the coiled coil of SMC3. [4] The central region of RAD21 is thought to be largely unstructured but contains several binding sites for regulators of cohesin. This includes a binding site for SA1 or SA2, [5] recognition motifs for separase cleavage [6] and a region that is competitively bound by PDS5A, PDS5B or NIPBL. [7] [8] [9] The C-terminal domain of RAD21 forms a winged helix that binds two β-sheets in the Smc1 head domain. [10]

Once RAD21 binds the SMC proteins, SCC3 can also associate with RAD21. When RAD21 binds on both SMC1 and SMC3, the cohesin complex forms a closed ring structure. The interfaces between the SMC subunits and RAD21 can open to allow DNA to pass in and out of the cohesin ring. [11]

While structures are available for many of the subunits and their interfaces, a structure of the entire cohesin complex has not been solved. Our knowledge of the conformation of cohesin comes largely from electron microscopy. These studies have revealed cohesin in numerous conformations including rings, elongated rods and most recently in a folded conformations. It is not known which conformation is predominant inside the cell and whether some are induced by sample preparation. [12]

Function

The cohesin complex regulates multiple vital cellular processes, such as:

  1. Sister chromatids cohesion during Mitosis and meiosis. It keeps the sister chromatids connected with each other during metaphase ensuring that, during cell division, each sister chromatid segregates to opposite poles. Without cohesin, the cell would be unable to control sister chromatid segregation since there would be no way of ensuring whether the spindle fiber attached on each sister chromatid is from a different pole. [13] [14] Other proteins also regulate this process together with cohesin. These are PDS5A, PDS5B, NIPBL and ESCO1 in mammalian cells. [14]
  2. Bipolar spindle apparatus assembly during mitosis. Cohesin ensures the attachment of spindle microtubules and sister kinetochores onto chromosomes. This is tighly related with the correct sisters chromatids seggregation towards the two spindle poles. Dysregulation in this process leads to premature chromosomes separation and multipolar spindles formation. [15] [16] The proteins Shugoshin 1 (or SGO1), Rae1 and NuMA are associated with cohesin in this assembly process. [17] [18]
  3. DNA damage checkpoint and repair. It participates in repairing double-strand breaks in DNA via homologus recombination, where the sister chromatid is used as a template for sequence reconstruction. [19]
  4. Recently many novel functions of cohesin have been discovered in many different cellular processes. Cohesin has been shown to be responsible for transcription regulation, DNA double strand break repair, chromosome condensation, pairing of homologous chromosomes during meiosis I, mono-orientation of sister kinetochores during meiosis I, non-homologous centromere coupling, chromosome architecture and rearrangement, DNA replication etc. [20]

Dissociation of sister chromatid cohesion

The anaphase promoting complex associated to Cdc20 (APC/C-cdc20) marks Securin (anaphase inhibitor) for degradation by the proteasome. Securin is cleaved at anaphase, following APC/C-cdc20 mediated degradation, and it renders separase (a protease, inhibited by the association with securin) to cleave the kleisin subunit. An alpha-kleisin is associated with the cohesin complex, linking both SMC 3 and SMC 1 together, with the exact kleisin varying between mitosis and meiosis (Scc1 and Rec8 respectively), and its cleavage ultimately leads to the removal of cohesin from chromosomes. [21]

Dissociation of sister chromatids cohesion defines anaphase onset, which establishes two sets of identical chromosomes at each pole of the cell (telophase). Then the two daughter cells separate, and a new round of the cell cycle freshly starts in each one, at the stage of G0. When cells are ready to divide, because cell size is big enough or because they receive the appropriate stimulus, [22] they activate the mechanism to enter into the G1 stage of cell cycle, and they duplicate most organelles during S (synthesis) phase, including their centrosome. Therefore, when the cell division process will end, each daughter cell will receive a complete set of organelles. At the same time, during S phase all cells must duplicate their DNA very precisely, a process termed DNA replication. Once DNA replication has finished, in eukaryotes the DNA molecule is compacted and condensed, to form the mitotic chromosomes, each one constituted by two sister chromatids, which stay held together by the establishment of cohesion between them; each chromatid is a complete DNA molecule, attached via microtubules to one of the two centrosomes of the dividing cell, located at opposed poles of the cell. To avoid premature sister chromatid separation, the APC/C is maintained in an inactive state bound to different molecules, which are part of a complex mechanism termed the spindle assembly checkpoint.

Mechanism of Sister Chromatid Cohesion

It is not clear how the cohesin ring links sister chromatids together. There are two possible scenarios:

  1. Cohesin subunits bind to each sister chromatid and form a bridge between the two.
  2. Since cohesin has a ring structure, it is able to encircle both sister chromatids.

Current evidence suggests that the second scenario is the most likely. Proteins that are essential for sister chromatid cohesion, such as Smc3 and Scc1, do not regulate the formation of covalent bonds between cohesin and DNA, indicating that DNA interaction is not sufficient for cohesion. [11] In addition, disturbing the ring structure of cohesin through cleavage of Smc3 or Scc1 triggers premature sister chromatid segregation in vivo. [23] This shows that the ring structure is important for cohesin's function.

Early studies suggested various ways in which cohesin may entrap DNA, [24] including as a monomer that holds both homologues together, and a "hand-cuff" model where two intertwining cohesin complexes each hold one sister chromatid. While some studies support the idea of a hand-cuff model, [24] the model is inconsistent with a number of experimental observations, [25] and is generally considered to entrap chromatin as a monomer.

Even though the ring hypothesis appears to be valid, there are still questions about the number of rings required to hold sister chromatids together. One possibility is that one ring surrounds the two chromatids. Another possibility involves the creation of a dimer where each ring surrounds one sister chromatid. The two rings are connected to each other through formation of a bridge that holds the two sister chromatids together.

The topology and structure of these subunits has been best characterized in budding yeast, [26] [27] but the sequence conservation of these proteins and biochemical and electron microscopic observations imply that cohesin complexes in other species are very similar in their structure, .

The cohesin complex is established during the initial stages of S-phase. The complexes associate with chromosomes before DNA replication occurs. Once cells start replicating their DNA, cohesin rings close and link the sister chromatids together. [11] Cohesin complexes must be present during S-phase in order for cohesion to take place. It is unclear, however, how cohesin is loaded on the chromosomes during G1. There are two proposed hypotheses so far:

  1. The ATPase domain of the SMC proteins interacts with DNA and this interaction initially mediates the loading of cohesin complexes on chromosomes.
  2. Several proteins aid in the loading process. For example, Scc2 and Scc4 are both required for cohesin to load in budding yeast.

Localization of cohesin rings

Cohesin binding along the chromosomal DNA is considered to be dynamic and its location changes based on gene transcription, specific DNA sequence and presence of chromosome-associated proteins. There are three possible scenarios:

  1. Cohesin location is influenced by the orientation of neighboring genes and it is most frequently located in areas of convergent transcription. Gene orientation depends on the direction of transcription and can be of three types: head-to-head, head-to-tail and tail-to-tail. The tail-to-tail configuration results in the convergence of transcription machinery. One hypothesis states that the RNA polymerase “pushes” cohesin along the DNA, causing them to move towards the direction of the RNA polymerases. Changing the transcription pattern of genes changes the location of cohesin indicating that localization of cohesin may depend on transcription. [28]
  2. In another model, chromatin loop extrusion is pushed by transcription generated supercoiling ensuring also that cohesin relocalizes quickly and loops grow with reasonable speed and in a good direction. In addition, the supercoiling-driven loop extrusion mechanism is consistent with earlier explanations proposing why topologically associating domains (TADs) flanked by convergent CTCF binding sites form more stable chromatin loops than TADs flanked by divergent CTCF binding sites. In this model, the supercoiling also stimulates enhancer promoter contacts and it is proposed that transcription of eRNA sends the first wave of supercoiling that can activate mRNA transcription in a given TAD. [29]
  3. A few cohesin rings are found in chromosome arms that have AT-rich DNA sequences indicating that DNA sequence may be an independent factor of cohesin binding. [28]
  4. Cohesin rings, especially in budding yeast, are also located in the region surrounding the centromere. [28] Two hypotheses may explain this: the presence of repetitive heterochromatic DNA in centromeres and the presence of chromosome-associated proteins. For example, Schizosaccharomyces pombe have multiple copies of specific heterochromatic DNA whose involvement in cohesion binding has been proven. Budding yeast lacks repetitive sequences and, therefore, requires a different mechanism for cohesion binding. Evidence suggests that binding of cohesin to the budding yeast centromere region depends on chromosome-associated proteins of the kinetochore that mediate cohesion association to pericentric regions (the kinetochore is an enhancer of pericentric cohesin binding). [30]

Cohesin and CTCF

Many chromatin loops are formed by so-called loop extrusion mechanism, when the cohesin ring moves actively along the two DNA double helices, translocating one of them with respect to the other. Thus, the loop can become smaller or larger. The loop extrusion process stops when cohesin encounters the architectural chromatin protein CTCF. The CTCF site needs to be in a proper orientation to stop cohesin.

Meiosis

Cohesin proteins SMC1β, SMC3, REC8 and STAG3 appear to participate in cohesion of sister chromatids throughout the meiotic process in human oocytes. [31] SMC1β, REC8 and STAG3 proteins are meiosis specific cohesins.

The STAG3 protein appears to be essential for female meiosis. A homozygous frameshift mutation in the Stag3 gene was identified in a large consanguineous family with premature ovarian failure. [32] Also, female mice deficient in STAG3 are sterile, and their fetal oocytes arrest at early prophase 1.

Evolution

Cohesin structure and function has been conserved in evolution. The SMC proteins are found in prokaryotes and have been conserved through evolution. The coils of SMC1 and SMC3 are conserved with an amino acid divergence of less than 0.5%. [33]

NameSaccharomyces cerevisiaeSchizosaccharomyces pombeDrosophilaVertebrates
Smc1Smc1Psm1DmSmc1 Smc1
Smc3Smc3Psm3DmSmc3 Smc3
Scc1Mcd1/Pds3Rad21DmRad21 Rad21
Scc3Scc3Psc3DmSASA1 and SA2

Clinical significance

The term "cohesinopathy" has been used to describe conditions affecting the cohesin complex. [34] [35] [36]

These conditions include:

See also

Related Research Articles

<span class="mw-page-title-main">Cell division</span> Process by which living cells divide

Cell division is the process by which a parent cell divides into two daughter cells. Cell division usually occurs as part of a larger cell cycle in which the cell grows and replicates its chromosome(s) before dividing. In eukaryotes, there are two distinct types of cell division: a vegetative division (mitosis), producing daughter cells genetically identical to the parent cell, and a cell division that produces haploid gametes for sexual reproduction (meiosis), reducing the number of chromosomes from two of each type in the diploid parent cell to one of each type in the daughter cells. In Mitosis is a part of the cell cycle, in which, replicated chromosomes are separated into two new nuclei. Cell division gives rise to genetically identical cells in which the total number of chromosomes is maintained. In general, mitosis is preceded by the S stage of interphase and is followed by telophase and cytokinesis; which divides the cytoplasm, organelles, and cell membrane of one cell into two new cells containing roughly equal shares of these cellular components. The different stages of mitosis all together define the M phase of an animal cell cycle—the division of the mother cell into two genetically identical daughter cells. To ensure proper progression through the cell cycle, DNA damage is detected and repaired at various checkpoints throughout the cycle. These checkpoints can halt progression through the cell cycle by inhibiting certain cyclin-CDK complexes. Meiosis undergoes two divisions resulting in four haploid daughter cells. Homologous chromosomes are separated in the first division of meiosis, such that each daughter cell has one copy of each chromosome. These chromosomes have already been replicated and have two sister chromatids which are then separated during the second division of meiosis. Both of these cell division cycles are used in the process of sexual reproduction at some point in their life cycle. Both are believed to be present in the last eukaryotic common ancestor.

<span class="mw-page-title-main">Condensin</span>

Condensins are large protein complexes that play a central role in chromosome assembly and segregation during mitosis and meiosis. Their subunits were originally identified as major components of mitotic chromosomes assembled in Xenopus egg extracts.

<span class="mw-page-title-main">Spindle checkpoint</span> Cell cycle checkpoint

The spindle checkpoint, also known as the metaphase-to-anaphase transition, the spindle assembly checkpoint (SAC), the metaphase checkpoint, or the mitotic checkpoint, is a cell cycle checkpoint during metaphase of mitosis or meiosis that prevents the separation of the duplicated chromosomes (anaphase) until each chromosome is properly attached to the spindle. To achieve proper segregation, the two kinetochores on the sister chromatids must be attached to opposite spindle poles. Only this pattern of attachment will ensure that each daughter cell receives one copy of the chromosome. The defining biochemical feature of this checkpoint is the stimulation of the anaphase-promoting complex by M-phase cyclin-CDK complexes, which in turn causes the proteolytic destruction of cyclins and proteins that hold the sister chromatids together.

<span class="mw-page-title-main">Kinetochore</span> Protein complex that allows microtubules to attach to chromosomes during cell division

A kinetochore is a disc-shaped protein structure associated with duplicated chromatids in eukaryotic cells where the spindle fibers attach during cell division to pull sister chromatids apart. The kinetochore assembles on the centromere and links the chromosome to microtubule polymers from the mitotic spindle during mitosis and meiosis. The term kinetochore was first used in a footnote in a 1934 Cytology book by Lester W. Sharp and commonly accepted in 1936. Sharp's footnote reads: "The convenient term kinetochore has been suggested to the author by J. A. Moore", likely referring to John Alexander Moore who had joined Columbia University as a freshman in 1932.

<span class="mw-page-title-main">Kim Nasmyth</span> British biochemist

Kim Ashley Nasmyth is an English geneticist, the Whitley Professor of Biochemistry at the University of Oxford, a Fellow of Trinity College, Oxford, former scientific director of the Research Institute of Molecular Pathology (IMP), and former head of the Department of Biochemistry, University of Oxford. He is best known for his work on the segregation of chromosomes during cell division.

<span class="mw-page-title-main">Separase</span> Mammalian protein found in Homo sapiens

Separase, also known as separin, is a cysteine protease responsible for triggering anaphase by hydrolysing cohesin, which is the protein responsible for binding sister chromatids during the early stage of anaphase. In humans, separin is encoded by the ESPL1 gene.

SMC complexes represent a large family of ATPases that participate in many aspects of higher-order chromosome organization and dynamics. SMC stands for Structural Maintenance of Chromosomes.

Mad2 is an essential spindle checkpoint protein. The spindle checkpoint system is a regulatory system that restrains progression through the metaphase-to-anaphase transition. The Mad2 gene was first identified in the yeast S. cerevisiae in a screen for genes which when mutated would confer sensitivity to microtubule poisons. The human orthologues of Mad2 were first cloned in a search for human cDNAs that would rescue the microtubule poison-sensitivity of a yeast strain in which a kinetochore binding protein was missing. The protein was shown to be present at unattached kinetochores and antibody inhibition studies demonstrated it was essential to execute a block in the metaphase-to-anaphase transition in response to the microtubule poison nocodazole. Subsequent cloning of the Xenopus laevis orthologue, facilitated by the sharing of the human sequence, allowed for the characterization of the mitotic checkpoint in egg extracts.

<span class="mw-page-title-main">Aurora kinase B</span> Protein

Aurora kinase B is a protein that functions in the attachment of the mitotic spindle to the centromere.

<span class="mw-page-title-main">SMC1A</span> Protein-coding gene in humans

Structural maintenance of chromosomes protein 1A (SMC1A) is a protein that in humans is encoded by the SMC1A gene. SMC1A is a subunit of the cohesin complex which mediates sister chromatid cohesion, homologous recombination and DNA looping. In somatic cells, cohesin is formed of SMC1A, SMC3, RAD21 and either SA1 or SA2 whereas in meiosis, cohesin is formed of SMC3, SMC1B, REC8 and SA3.

Chromosome segregation is the process in eukaryotes by which two sister chromatids formed as a consequence of DNA replication, or paired homologous chromosomes, separate from each other and migrate to opposite poles of the nucleus. This segregation process occurs during both mitosis and meiosis. Chromosome segregation also occurs in prokaryotes. However, in contrast to eukaryotic chromosome segregation, replication and segregation are not temporally separated. Instead segregation occurs progressively following replication.

<span class="mw-page-title-main">RAD21</span> Protein-coding gene in humans

Double-strand-break repair protein rad21 homolog is a protein that in humans is encoded by the RAD21 gene. RAD21, an essential gene, encodes a DNA double-strand break (DSB) repair protein that is evolutionarily conserved in all eukaryotes from budding yeast to humans. RAD21 protein is a structural component of the highly conserved cohesin complex consisting of RAD21, SMC1A, SMC3, and SCC3 [ STAG1 (SA1) and STAG2 (SA2) in multicellular organisms] proteins, involved in sister chromatid cohesion.

<span class="mw-page-title-main">SMC3</span> Protein-coding gene in humans

Structural maintenance of chromosomes protein 3 (SMC3) is a protein that in humans is encoded by the SMC3 gene. SMC3 is a subunit of the Cohesin complex which mediates sister chromatid cohesion, homologous recombination and DNA looping. Cohesin is formed of SMC3, SMC1, RAD21 and either SA1 or SA2. In humans, SMC3 is present in all cohesin complexes whereas there are multiple paralogs for the other subunits.

<span class="mw-page-title-main">STAG2</span> Protein-coding gene in humans

Cohesin subunit SA-2 (SA2) is a protein that in humans is encoded by the STAG2 gene. SA2 is a subunit of the Cohesin complex which mediates sister chromatid cohesion, homologous recombination and DNA looping. In somatic cells cohesin is formed of SMC3, SMC1, RAD21 and either SA1 or SA2 whereas in meiosis, cohesin is formed of SMC3, SMC1B, REC8 and SA3.

<span class="mw-page-title-main">WAPAL</span> Protein-coding gene in the species Homo sapiens

Wings apart-like protein homolog (WAPL) is a protein that in humans is encoded by the WAPAL gene. WAPL is a key regulator of the Cohesin complex which mediates sister chromatid cohesion, homologous recombination and DNA looping. Cohesin is formed of SMC3, SMC1, RAD21 and either SA1 or SA2. Cohesin has a ring-like arrangement and it is thought that it associates with the chromosome by entrapping it whether as a loop of DNA, a single strand or a pair of sister chromosomes. WAPL forms a complex with PDS5A or PDS5B and releases cohesin from DNA by opening the interface between SMC3 and RAD21.

<span class="mw-page-title-main">REC8</span> Protein-coding gene in the species Homo sapiens

Meiotic recombination protein REC8 homolog is a protein that in humans is encoded by the REC8 gene.

<span class="mw-page-title-main">STAG1</span> Protein-coding gene in the species Homo sapiens

Cohesin subunit SA-1 (SA1) is a protein that in humans is encoded by the STAG1 gene. SA1 is a subunit of the Cohesin complex which mediates sister chromatid cohesion, homologous recombination and DNA looping. In somatic cells cohesin is formed of SMC3, SMC1, RAD21 and either SA1 or SA2 whereas in meiosis, cohesin is formed of SMC3, SMC1B, REC8 and SA3. There is a nonprofit community formed for those with a STAG1 Gene mutation at www.stag1gene.org.

Sister chromatid cohesion refers to the process by which sister chromatids are paired and held together during certain phases of the cell cycle. Establishment of sister chromatid cohesion is the process by which chromatin-associated cohesin protein becomes competent to physically bind together the sister chromatids. In general, cohesion is established during S phase as DNA is replicated, and is lost when chromosomes segregate during mitosis and meiosis. Some studies have suggested that cohesion aids in aligning the kinetochores during mitosis by forcing the kinetochores to face opposite cell poles.

<span class="mw-page-title-main">SMC1B</span> Protein-coding gene in the species Homo sapiens

Structural maintenance of chromosomes protein 1B (SMC-1B) is a protein that in humans is encoded by the SMC1B gene. SMC proteins engage in chromosome organization and can be broken into 3 groups based on function which are cohesins, condensins, and DNA repair. SMC-1B belongs to a family of proteins required for chromatid cohesion and DNA recombination during meiosis and mitosis. SMC1B protein appears to participate with other cohesins REC8, STAG3 and SMC3 in sister-chromatid cohesion throughout the whole meiotic process in human oocytes.

<span class="mw-page-title-main">Frank Uhlmann</span>

Frank Uhlmann FRS is a group leader at the Francis Crick Institute in London.

References

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  24. 1 2 Zhang N, Kuznetsov SG, Sharan SK, Li K, Rao PH, Pati D (December 2008). "A handcuff model for the cohesin complex". The Journal of Cell Biology. 183 (6): 1019–31. doi:10.1083/jcb.200801157. PMC   2600748 . PMID   19075111.
  25. ↑ Nasmyth K (October 2011). "Cohesin: a catenase with separate entry and exit gates?". Nature Cell Biology. 13 (10): 1170–7. doi:10.1038/ncb2349. PMID   21968990. S2CID   25382204.
  26. ↑ Haering, CH; Löwe, J; Hochwagen, A; Nasmyth, K (April 2002). "Molecular architecture of SMC proteins and the yeast cohesin complex". Molecular Cell. 9 (4): 773–88. doi: 10.1016/s1097-2765(02)00515-4 . PMID   11983169.
  27. ↑ Haering, CH; Farcas, AM; Arumugam, P; Metson, J; Nasmyth, K (17 July 2008). "The cohesin ring concatenates sister DNA molecules" (PDF). Nature. 454 (7202): 297–301. Bibcode:2008Natur.454..297H. doi:10.1038/nature07098. PMID   18596691. S2CID   1190883.
  28. 1 2 3 Ross KE, Cohen-Fix O (July 2004). "Molecular biology: cohesins slip sliding away". Nature. 430 (6999): 520–1. Bibcode:2004Natur.430..520R. doi: 10.1038/430520b . PMID   15282594. S2CID   52818523.
  29. ↑ Racko D, Benedetti F, Dorier J, Stasiak A (13 November 2017). "Transcription-induced supercoiling as the driving force of chromatin loop extrusion during formation of TADs in interphase chromosomes". Nucleic Acids Res. 46 (4): 1648–1660. doi:10.1093/nar/gkx1123. PMC   5829651 . PMID   29140466.
  30. ↑ Weber SA, Gerton JL, Polancic JE, DeRisi JL, Koshland D, Megee PC (September 2004). "The kinetochore is an enhancer of pericentric cohesin binding". PLOS Biology. 2 (9): E260. doi: 10.1371/journal.pbio.0020260 . PMC   490027 . PMID   15309047.
  31. ↑ Garcia-Cruz R, Brieño MA, Roig I, Grossmann M, Velilla E, Pujol A, Cabero L, Pessarrodona A, Barbero JL, Garcia Caldés M (September 2010). "Dynamics of cohesin proteins REC8, STAG3, SMC1 beta and SMC3 are consistent with a role in sister chromatid cohesion during meiosis in human oocytes". Human Reproduction. 25 (9): 2316–27. doi:10.1093/humrep/deq180. PMID   20634189.
  32. ↑ Caburet S, Arboleda VA, Llano E, Overbeek PA, Barbero JL, Oka K, Harrison W, Vaiman D, Ben-Neriah Z, García-Tuñón I, Fellous M, Pendás AM, Veitia RA, Vilain E (March 2014). "Mutant cohesin in premature ovarian failure". The New England Journal of Medicine. 370 (10): 943–949. doi:10.1056/NEJMoa1309635. PMC   4068824 . PMID   24597867.
  33. ↑ White GE, Erickson HP (2009). "The coiled coils of cohesin are conserved in animals, but not in yeast". PLOS ONE. 4 (3): e4674. Bibcode:2009PLoSO...4.4674W. doi: 10.1371/journal.pone.0004674 . PMC   2650401 . PMID   19262687.
  34. ↑ Gard S, Light W, Xiong B, Bose T, McNairn AJ, Harris B, Fleharty B, Seidel C, Brickner JH, Gerton JL (November 2009). "Cohesinopathy mutations disrupt the subnuclear organization of chromatin". The Journal of Cell Biology. 187 (4): 455–62. doi:10.1083/jcb.200906075. PMC   2779225 . PMID   19948494.
  35. ↑ van der Lelij P, Chrzanowska KH, Godthelp BC, Rooimans MA, Oostra AB, Stumm M, Zdzienicka MZ, Joenje H, de Winter JP (February 2010). "Warsaw breakage syndrome, a cohesinopathy associated with mutations in the XPD helicase family member DDX11/ChlR1". American Journal of Human Genetics. 86 (2): 262–6. doi:10.1016/j.ajhg.2010.01.008. PMC   2820174 . PMID   20137776.
  36. ↑ van der Lelij P, Godthelp BC, van Zon W, van Gosliga D, Oostra AB, Steltenpool J, de Groot J, Scheper RJ, Wolthuis RM, Waisfisz Q, Darroudi F, Joenje H, de Winter JP (September 2009). Warburton PE (ed.). "The cellular phenotype of Roberts syndrome fibroblasts as revealed by ectopic expression of ESCO2". PLOS ONE. 4 (9): e6936. Bibcode:2009PLoSO...4.6936V. doi: 10.1371/journal.pone.0006936 . PMC   2734174 . PMID   19738907.

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