Establishment of sister chromatid cohesion

Last updated

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. [1]

Contents

Cohesin loading

Cohesin first associates with the chromosomes during G1 phase. The cohesin ring is composed of two SMC (structural maintenance of chromosomes) proteins and two additional Scc proteins. Cohesin may originally interact with chromosomes via the ATPase domains of the SMC proteins. In yeast, the loading of cohesin on the chromosomes depends on proteins Scc2 and Scc4. [2]

Cohesin interacts with the chromatin at specific loci. High levels of cohesin binding are observed at the centromere. Cohesin is also loaded at cohesin attachment regions (CARs) along the length of the chromosomes. CARs are approximately 500-800 base pair regions spaced at approximately 9 kilobase intervals along the chromosomes. In yeast, CARs tend to be rich in adenine-thymine base pairs. CARs are independent of origins of replication. [1] [3]

Establishment of cohesion

Establishment of cohesion refers to the process by which chromatin-associated cohesin becomes cohesion-competent. Chromatin association of cohesin is not sufficient for cohesion. Cohesin must undergo subsequent modification ("establishment") to be capable of physically holding the sister chromosomes together. [4] Though cohesin can associate with chromatin earlier in the cell cycle, cohesion is established during S phase. Early data suggesting that S phase is crucial to cohesion was based on the fact that after S phase, sister chromatids are always found in the bound state. Tying establishment to DNA replication allows the cell to institute cohesion as soon as the sister chromatids are formed. This solves the problem of how the cell might properly identify and pair sister chromatids by ensuring that the sister chromatids are never separate once replication has occurred. [1]

The Eco1/Ctf7 gene (yeast) was one of the first genes to be identified as specifically required for the establishment of cohesion. Eco1 must be present in S phase to establish cohesion, but its continued presence is not required to maintain cohesion. [1] Eco1 interacts with many proteins directly involved in DNA replication, including the processivity clamp PCNA, clamp loader subunits, and a DNA helicase. Though Eco1 contains several functional domains, it is the acetyltransferase activity of the protein which is crucial for establishment of cohesion. During S phase, Eco1 acetylates lysine residues in the Smc3 subunit of cohesin. Smc3 remains acetylated until at least anaphase. [4] Once cohesin has been removed from the chromatin, Smc3 is deacetylated by Hos1. [5]

The Pds5 gene was also identified in yeast as necessary for the establishment of cohesion. In humans, the gene has two homologs, Pds5A and Pds5B. Pds5 interacts with chromatin-associated cohesin. Pds5 is not strictly establishment-specific, as Pds5 is necessary for maintenance of cohesion during G2 and M phase. The loss of Pds5 negates the requirement for Eco1. As such, Pds5 is often termed an "anti-establishment" factor. [4]

In addition to interacting with cohesin, Pds5 also interacts with Wapl (wings apart-like), another protein that has been implicated in the regulation of sister chromatid cohesion. Human Wapl binds cohesin through the Scc cohesin subunits (in humans, Scc1 and SA1). Wapl has been tied to the loss of cohesin from the chromatids during M phase. [6] Wapl interacts with Pds5 through phenylalanine-glycine-phenylalanine (FGF) sequence motifs. [7]

One model of establishment of cohesion suggests that establishment is mediated by the replacement of Wapl in the Wapl-Pds5-cohesin complex with the Sororin protein. Like Wapl, Sororin contains an FGF domain and is capable of interacting with Pds5. In this model, put forward by Nishiyama et al., Wapl interacts with Pds5 and cohesin during G1, before establishment. During S phase, Eco1 (Esco1/Esco2 in humans) acetylates Smc3. This results in recruitment of Sororin. Sororin then replaces Wapl in the Pds5-cohesin complex. This new complex is the established, cohesion-competent cohesin state. At entry to mitosis, Sororin is phosphorylated and replaced again by Wapl, leading to loss of cohesion. [8] Sororin also has chromatin binding activity independent of its ability to mediate cohesion. [9]

Meiosis

Cohesion proteins SMC1ß, SMC3, REC8 and STAG3 appear to participate in the cohesion of sister chromatids throughout the meiotic process in human oocytes. [10] SMC1ß, REC8 and STAG3 are meiosis specific cohesin proteins. The STAG3 protein is essential for female meiosis and fertility. [11] Cohesins are involved in meiotic recombination. [12]

Ties to DNA replication

A growing body of evidence ties establishment of cohesion to DNA replication. As mentioned above, functional coupling of these two processes prevents the cell from having to later distinguish which chromosomes are sisters by ensuring that the sister chromatids are never separate after replication. [1]

Another significant tie between DNA replication and cohesion pathways is through Replication Factor C (RFC). This complex, the "clamp loader," is responsible for loading PCNA onto DNA. An alternative form of RFC is required for sister chromatin cohesion. This alternative form is composed of core RFC proteins RFC2, RFC3, RFC4, and RFC5, but replaces the RFC1 protein with cohesion specific proteins Ctf8, Ctf18, and Dcc1. A similar function-specific alternative RFC (replacing RFC1 with Rad24) plays a role in the DNA damage checkpoint. The presence of an alternative RFC in the cohesion pathway can be interpreted as evidence in support of the polymerase switch model for cohesion establishment. [13] Like the non-cohesion RFC, the cohesion RFC loads PCNA onto DNA. [14]

Some of the evidence tying cohesion and DNA replication comes from the multiple interactions of Eco1. Eco1 interacts with PCNA, RFC subunits, and a DNA helicase, Chl1, either physically or genetically. [4] [15] Studies have also found replication-linked proteins which influence cohesion independent of Eco1. [16] The Ctf18 subunit of the cohesion-specific RFC can interact with cohesin subunits Smc1 and Scc1. [14]

Hypothesized model for the pro- and anti-establishment functions of replication factor C complexes in sister chromatid cohesion. Maradeo2010Fig10.tif
Hypothesized model for the pro- and anti-establishment functions of replication factor C complexes in sister chromatid cohesion.

Polymerase switch model

Though the protein was originally identified as a Topoisomerase I redundant factor, the TRF4 gene product was later shown to be required for sister chromatid cohesion. Wang et al. showed that Trf4 is actually a DNA polymerase, which they called Polymerase κ. [17] This polymerase is also referred to as Polymerase σ. In the same paper in which they identified Pol σ, Wang et al. suggested a polymerase switch model for establishment of cohesion. [17] In this model, upon reaching a CAR, the cell switches DNA polymerases in a mechanism similar to that used in Okazaki fragment synthesis. The cell off-loads the processive replication polymerase and instead uses Pol σ for synthesis of the CAR region. It has been suggested that the cohesion-specific RFC could function in off-loading or on-loading PNCA and polymerases in such a switch. [1]

Ties to DNA damage pathways

Changes in patterns of sister chromatid cohesion have been observed in cases of DNA damage. Cohesin is required for repair of DNA double-strand breaks (DSBs). One mechanism of DSB repair, homologous recombination (HR), requires the presence of the sister chromatid for repair at the break site. Thus, it is possible that cohesion is required for this process because it ensures that the sister chromatids are physically close enough to undergo HR. DNA damage can lead to cohesin loading at non-CAR sites and establishment of cohesion at these sites even during G2 phase. In the presence of ionizing radiation (IR), the Smc1 subunit of cohesin is phosphorylated by the ataxia telangiectasia mutated (ATM) kinase. [18] ATM is a key kinase in the DNA damage checkpoint. Defects in cohesion can increase genome instability, [19] a result consistent with the ties between cohesion and DNA damage pathways.

In the bacterium Escherichia coli , repair of mitomycin C-induced DNA damages occurs by a sister chromatid cohesion process involving the RecN protein. [20] Sister chromatid interaction followed by homologous recombination appears to significantly contribute to the repair of DNA double-strand damages.

Medical relevance

Defects in the establishment of sister chromatid cohesion have serious consequences for the cell and are therefore tied to many human diseases. Failure to establish cohesion correctly or inappropriate loss of cohesion can lead to missegregation of chromosomes during mitosis, which results in aneuploidy. The loss of the human homologs of core cohesin proteins or of Eco1, Pds5, Wapl, Sororin, or Scc2 has been tied to cancer. Mutations affecting cohesion and establishment of cohesion are also responsible for Cornelia de Lange Syndrome and Roberts Syndrome. Diseases arising from defects in cohesin or other proteins involved in sister chromatid cohesion are referred to as cohesinopathies. [19]

Cornelia de Lange Syndrome

Genetic alterations in genes NIPBL , SMC1A , SMC3 , RAD21 and HDAC8 are associated with Cornelia de Lange Syndrome. [21] The proteins encoded by these genes all function in the chromosome cohesion pathway that is employed in the cohesion of sister chromatids during mitosis, DNA repair, chromosome segregation and the regulation of developmental gene expression. Defects in these functions likely underlie many of the features of Cornelia de Lang Syndrome.

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 cell biology, mitosis (/maɪˈtoʊsɪs/) 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 often 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 mitotic (M) phase of animal cell cycle—the division of the mother cell into two genetically identical daughter cells. Meiosis results in four haploid daughter cells by undergoing one round of DNA replication followed by two divisions. Homologous chromosomes are separated in the first division, and sister chromatids are separated in the second division. 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">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 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">Separase</span>

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.

<span class="mw-page-title-main">Cohesin</span> Protein complex that regulates the separation of sister chromatids during cell division

Cohesin is a protein complex that mediates sister chromatid cohesion, homologous recombination, and DNA looping. Cohesin is formed of SMC3, SMC1, SCC1 and SCC3. 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.

<span class="mw-page-title-main">Eukaryotic DNA replication</span> DNA replication in eukaryotic organisms

Eukaryotic DNA replication is a conserved mechanism that restricts DNA replication to once per cell cycle. Eukaryotic DNA replication of chromosomal DNA is central for the duplication of a cell and is necessary for the maintenance of the eukaryotic genome.

<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.

<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">RFC2</span> Protein-coding gene in the species Homo sapiens

Replication factor C subunit 2 is a protein that in humans is encoded by the RFC2 gene.

<span class="mw-page-title-main">RFC3</span> Protein-coding gene in the species Homo sapiens

Replication factor C subunit 3 is a protein that in humans is encoded by the RFC3 gene.

<span class="mw-page-title-main">RFC5</span> Protein-coding gene in the species Homo sapiens

Replication factor C subunit 5 is a protein that in humans is encoded by the RFC5 gene.

<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">PDS5B</span> Protein-coding gene in the species Homo sapiens

Sister chromatid cohesion protein PDS5 homolog B(PDS5B) is a protein that in humans is encoded by the PDS5B gene. It is a regulatory subunit of the Cohesin complex which mediates sister chromatid cohesion, homologous recombination and DNA looping. The core cohesin complex is formed of SMC3, SMC1, RAD21 and either SA1 or SA2. PDS5 associates with WAPL to stimulate the release of cohesin from DNA but during DNA replication PDS5 promotes acetylation of SMC3 by ESCO1 and ESCO2.

<span class="mw-page-title-main">CTF8</span> Protein-coding gene in the species Homo sapiens

Chromosome transmission fidelity protein 8 homolog is a protein that in humans is encoded by the CHTF8 gene.

<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">CHTF18</span> Protein-coding gene in the species Homo sapiens

Chromosome transmission fidelity protein 18 homolog is a protein that in humans is encoded by the CHTF18 gene.

<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. SMC1ß 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

  1. 1 2 3 4 5 6 Wang, Zhenghe; Christman, Michael F. (2001). "Replication-Related Activities Establish Cohesion Between Sister Chromatids". Cell Biochemistry and Biophysics. 35 (3): 289–301. doi:10.1385/cbb:35:3:289. PMID   11894848. S2CID   12433941.
  2. ↑ Morgan, David O. (2007). The Cell Cycle, Principles of Control. New Science Press Ltd.
  3. ↑ Cohen-Fix, Orna (2001). "The Making and Breaking of Sister Chromatid Cohesion". Cell. 106 (2): 137–140. doi: 10.1016/s0092-8674(01)00439-1 . PMID   11511341.
  4. 1 2 3 4 Skibbens, Robert V. (2009). "Establishment of Sister Chromatid Cohesion". Current Biology. 19 (24): R1126–R1132. doi:10.1016/j.cub.2009.10.067. PMC   4867117 . PMID   20064425.
  5. ↑ Borges, Vanessa; Lehane, Chris; Lopez-Serra, Lidia; Flynn, Helen; Skehel, Mark; Ben-Shahar, Tom Rolef; Uhlmann, Frank (2010). "Hos1 Deacetylates Smc3 to Close the Cohesin Acetylation Cycle". Molecular Cell. 39 (5): 677–688. doi: 10.1016/j.molcel.2010.08.009 . PMID   20832720.
  6. ↑ Gandhi, Rita; Gillespie, Peter J.; Hirano, Tatsuya (2006). "Human Wapl is a Cohesin-Binding Protein that Promotes Sister-Chromatid Resolution in Mitotic Prophase". Current Biology. 16 (24): 2406–2417. doi:10.1016/j.cub.2006.10.061. PMC   1850625 . PMID   17112726.
  7. ↑ Shintomi, K.; Hirano, T. (2009). "Releasing cohesin from chromosome arms in early mitosis: Opposing actions of Wapl-Pds5 and Sgo1". Genes & Development. 23 (18): 2224–2236. doi:10.1101/gad.1844309. PMC   2751989 . PMID   19696148.
  8. ↑ Nishiyama, Tomoko; Ladurner, Rene; Schmitz, Julia; Kreidl, Emanuel; Schleiffer, Alexander; Bhaskara, Venugopal; Bando, Masashige; Shirahige, Katsuhiko; Hyman, Anthony A.; Mechtler, Karl; Peters, Jan-Michael (2010). "Sororin Mediates Sister Chromatid Cohesion by Antagonizing Wapl". Cell. 143 (5): 737–749. doi: 10.1016/j.cell.2010.10.031 . PMID   21111234.
  9. ↑ Wu, Frank M.; Nguyen, Judy V.; Rankin, Susannah (2011). "A Conserved Motif at the C Terminus of Sororin is Required for Sister Chromatid Cohesion". Journal of Biological Chemistry. 286 (5): 3579–3586. doi: 10.1074/jbc.M110.196758 . PMC   3030362 . PMID   21115494.
  10. ↑ Garcia-Cruz R, Brieño MA, Roig I, Grossmann M, Velilla E, Pujol A, Cabero L, Pessarrodona A, Barbero JL, Garcia Caldés M (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". Hum. Reprod. 25 (9): 2316–27. doi: 10.1093/humrep/deq180 . PMID   20634189.
  11. ↑ 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 (2014). "Mutant cohesin in premature ovarian failure". N. Engl. J. Med. 370 (10): 943–949. doi:10.1056/NEJMoa1309635. PMC   4068824 . PMID   24597867.
  12. ↑ Kusch, T. (2015). "Brca2-Pds5 complexes mobilize persistent meiotic recombination sites to the nuclear envelope". Journal of Cell Science. 128 (4): 717–727. doi: 10.1242/jcs.159988 . PMID   25588834. S2CID   7093288.
  13. ↑ Mayer, Melanie L.; Gygi, Steven P.; Aebersold, Ruedi; Hieter, Philip (2001). "Identification of RFC(Ctf18p, Ctf8p, Dcc1p)". Molecular Cell. 7 (5): 959–970. doi: 10.1016/s1097-2765(01)00254-4 . PMID   11389843.
  14. 1 2 Bermudez, Vladimir P.; Maniwa, Yoshimasa; Tappin, Inger; Ozato, Keiko; Yokomori, Kyoko; Hurwitz, Jerard (2003). "The alternative Ctf18-Dcc1-Ctf8-replication factor C complex required for sister chromatid cohesion loads proliferating cell nuclear antigen onto DNA". Proceedings of the National Academy of Sciences. 100 (18): 10237–42. Bibcode:2003PNAS..10010237B. doi: 10.1073/pnas.1434308100 . PMC   193545 . PMID   12930902.
  15. ↑ Skibbens, R. V. (2004). "Chl1p, a DNA Helicase-Like Protein in Budding Yeast, Functions in Sister-Chromatid Cohesion". Genetics. 166 (1): 33–42. doi:10.1534/genetics.166.1.33. PMC   1470669 . PMID   15020404.
  16. 1 2 Maradeo, Marie E.; Skibbens, Robert V. (2010). "Replication Factor C Complexes Play Unique Pro- and Anti-Establishment Roles in Sister Chromatid Cohesion". PLOS ONE. 5 (10): e15381. Bibcode:2010PLoSO...515381M. doi: 10.1371/journal.pone.0015381 . PMC   2965161 . PMID   21060875.
  17. 1 2 Wang, Zhenghe; Castaño, Irene B.; De Las Peñas, Alejandro; Adams, Carrie; Christman, Michael F. (2000). "Pol κ: A DNA Polymerase Required for Sister Chromatid Cohesion". Science. 289 (5480): 774–9. Bibcode:2000Sci...289..774W. doi:10.1126/science.289.5480.774. PMID   10926539.
  18. ↑ Watrin, Erwan; Peters, Jan-Michael (2006). "Cohesin and DNA damage repair". Experimental Cell Research. 312 (14): 2687–2693. doi:10.1016/j.yexcr.2006.06.024. PMID   16876157.
  19. 1 2 Mannini, Linda; Menga, Stefania; Musio, Antonio (2010). "The expanding universe of cohesin functions: A new genome stability caretaker involved in human disease and cancer". Human Mutation. 31 (6): 623–630. doi: 10.1002/humu.21252 . PMID   20513141. S2CID   27361281.
  20. ↑ Vickridge E, Planchenault C, Cockram C, Junceda IG, Espéli O (2017). "Management of E. coli sister chromatid cohesion in response to genotoxic stress". Nat Commun. 8: 14618. Bibcode:2017NatCo...814618V. doi:10.1038/ncomms14618. PMC   5343486 . PMID   28262707.
  21. ↑ Boyle MI, Jespersgaard C, Brøndum-Nielsen K, Bisgaard AM, Tümer Z (2015). "Cornelia de Lange syndrome". Clin. Genet. 88 (1): 1–12. doi:10.1111/cge.12499. PMID   25209348. S2CID   37580405.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.