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1
Sapkota, Hem, Emilia Wasiak, John R. Daum, and Gary J. Gorbsky. "Multiple determinants and consequences of cohesion fatigue in mammalian cells." Molecular Biology of the Cell 29, no. 15 (August 2018): 1811–24. http://dx.doi.org/10.1091/mbc.e18-05-0315.
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Cells delayed in metaphase with intact mitotic spindles undergo cohesion fatigue, where sister chromatids separate asynchronously, while cells remain in mitosis. Cohesion fatigue requires release of sister chromatid cohesion. However, the pathways that breach sister chromatid cohesion during cohesion fatigue remain unknown. Using moderate-salt buffers to remove loosely bound chromatin cohesin, we show that “cohesive” cohesin is not released during chromatid separation during cohesion fatigue. Using a regulated protein heterodimerization system to lock different cohesin ring interfaces at specific times in mitosis, we show that the Wapl-mediated pathway of cohesin release is not required for cohesion fatigue. By manipulating microtubule stability and cohesin complex integrity in cell lines with varying sensitivity to cohesion fatigue, we show that rates of cohesion fatigue reflect a dynamic balance between spindle pulling forces and resistance to separation by interchromatid cohesion. Finally, while massive separation of chromatids in cohesion fatigue likely produces inviable cell progeny, we find that short metaphase delays, leading to partial chromatid separation, predispose cells to chromosome missegregation. Thus, complete separation of one or a few chromosomes and/or partial separation of sister chromatids may be an unrecognized but common source of chromosome instability that perpetuates the evolution of malignant cells in cancer.
2
Mishra, Prashant K., Sultan Ciftci-Yilmaz, David Reynolds, Wei-Chun Au, Lars Boeckmann, Lauren E. Dittman, Ziad Jowhar, et al. "Polo kinase Cdc5 associates with centromeres to facilitate the removal of centromeric cohesin during mitosis." Molecular Biology of the Cell 27, no. 14 (July 15, 2016): 2286–300. http://dx.doi.org/10.1091/mbc.e16-01-0004.
Full textAbstract:
Sister chromatid cohesion is essential for tension-sensing mechanisms that monitor bipolar attachment of replicated chromatids in metaphase. Cohesion is mediated by the association of cohesins along the length of sister chromatid arms. In contrast, centromeric cohesin generates intrastrand cohesion and sister centromeres, while highly cohesin enriched, are separated by >800 nm at metaphase in yeast. Removal of cohesin is necessary for sister chromatid separation during anaphase, and this is regulated by evolutionarily conserved polo-like kinase (Cdc5 in yeast, Plk1 in humans). Here we address how high levels of cohesins at centromeric chromatin are removed. Cdc5 associates with centromeric chromatin and cohesin-associated regions. Maximum enrichment of Cdc5 in centromeric chromatin occurs during the metaphase-to-anaphase transition and coincides with the removal of chromosome-associated cohesin. Cdc5 interacts with cohesin in vivo, and cohesin is required for association of Cdc5 at centromeric chromatin. Cohesin removal from centromeric chromatin requires Cdc5 but removal at distal chromosomal arm sites does not. Our results define a novel role for Cdc5 in regulating removal of centromeric cohesins and faithful chromosome segregation.
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Oliveira, Raquel A., and Kim Nasmyth. "Getting through anaphase: splitting the sisters and beyond." Biochemical Society Transactions 38, no. 6 (November 24, 2010): 1639–44. http://dx.doi.org/10.1042/bst0381639.
Full textAbstract:
Sister-chromatid cohesion, thought to be primarily mediated by the cohesin complex, is essential for chromosome segregation. The forces holding the two sisters resist the tendency of microtubules to prematurely pull sister DNAs apart and thereby prevent random segregation of the genome during mitosis, and consequent aneuploidy. By counteracting the spindle pulling forces, cohesion between the two sisters generates the tension necessary to stabilize microtubule–kinetochore attachments. Upon entry into anaphase, however, the linkages that hold the two sister DNAs must be rapidly destroyed to allow physical separation of chromatids. Anaphase cells must therefore possess mechanisms that ensure faithful segregation of single chromatids that are now attached stably to the spindle in a manner no longer dependent on tension. In the present review, we discuss the nature of the cohesive forces that hold sister chromatids together, the mechanisms that trigger their physical separation, and the anaphase-specific changes that ensure proper segregation of single chromatids during the later stages of mitosis.
4
Stanyte, Rugile, Johannes Nuebler, Claudia Blaukopf, Rudolf Hoefler, Roman Stocsits, Jan-Michael Peters, and Daniel W. Gerlich. "Dynamics of sister chromatid resolution during cell cycle progression." Journal of Cell Biology 217, no. 6 (April 25, 2018): 1985–2004. http://dx.doi.org/10.1083/jcb.201801157.
Full textAbstract:
Faithful genome transmission in dividing cells requires that the two copies of each chromosome’s DNA package into separate but physically linked sister chromatids. The linkage between sister chromatids is mediated by cohesin, yet where sister chromatids are linked and how they resolve during cell cycle progression has remained unclear. In this study, we investigated sister chromatid organization in live human cells using dCas9-mEGFP labeling of endogenous genomic loci. We detected substantial sister locus separation during G2 phase irrespective of the proximity to cohesin enrichment sites. Almost all sister loci separated within a few hours after their respective replication and then rapidly equilibrated their average distances within dynamic chromatin polymers. Our findings explain why the topology of sister chromatid resolution in G2 largely reflects the DNA replication program. Furthermore, these data suggest that cohesin enrichment sites are not persistent cohesive sites in human cells. Rather, cohesion might occur at variable genomic positions within the cell population.
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Chen, Yu-Fan, Chia-Ching Chou, and Marc R. Gartenberg. "Determinants of Sir2-Mediated, Silent Chromatin Cohesion." Molecular and Cellular Biology 36, no. 15 (May 16, 2016): 2039–50. http://dx.doi.org/10.1128/mcb.00057-16.
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Cohesin associates with distinct sites on chromosomes to mediate sister chromatid cohesion. Single cohesin complexes are thought to bind by encircling both sister chromatids in a topological embrace. Transcriptionally repressed chromosomal domains in the yeastSaccharomyces cerevisiaerepresent specialized sites of cohesion where cohesin binds silent chromatin in a Sir2-dependent fashion. In this study, we investigated the molecular basis for Sir2-mediated cohesion. We identified a cluster of charged surface residues of Sir2, collectively termed the EKDK motif, that are required for cohesin function. In addition, we demonstrated that Esc8, a Sir2-interacting factor, is also required for silent chromatin cohesion. Esc8 was previously shown to associate with Isw1, the enzymatic core of ISW1 chromatin remodelers, to form a variant of the ISW1a chromatin remodeling complex. WhenESC8was deleted or the EKDK motif was mutated, cohesin binding at silenced chromatin domains persisted but cohesion of the domains was abolished. The data are not consistent with cohesin embracing both sister chromatids within silent chromatin domains. Transcriptional silencing remains largely intact in strains lackingESC8or bearing EKDK mutations, indicating that silencing and cohesion are separable functions of Sir2 and silent chromatin.
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van Schie, Janne J. M., and Job de Lange. "The Interplay of Cohesin and the Replisome at Processive and Stressed DNA Replication Forks." Cells 10, no. 12 (December 8, 2021): 3455. http://dx.doi.org/10.3390/cells10123455.
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The cohesin complex facilitates faithful chromosome segregation by pairing the sister chromatids after DNA replication until mitosis. In addition, cohesin contributes to proficient and error-free DNA replication. Replisome progression and establishment of sister chromatid cohesion are intimately intertwined processes. Here, we review how the key factors in DNA replication and cohesion establishment cooperate in unperturbed conditions and during DNA replication stress. We discuss the detailed molecular mechanisms of cohesin recruitment and the entrapment of replicated sister chromatids at the replisome, the subsequent stabilization of sister chromatid cohesion via SMC3 acetylation, as well as the role and regulation of cohesin in the response to DNA replication stress.
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Yan, Rihui, Sharon E. Thomas, Jui-He Tsai, Yukihiro Yamada, and Bruce D. McKee. "SOLO: a meiotic protein required for centromere cohesion, coorientation, and SMC1 localization in Drosophila melanogaster." Journal of Cell Biology 188, no. 3 (February 8, 2010): 335–49. http://dx.doi.org/10.1083/jcb.200904040.
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Sister chromatid cohesion is essential to maintain stable connections between homologues and sister chromatids during meiosis and to establish correct centromere orientation patterns on the meiosis I and II spindles. However, the meiotic cohesion apparatus in Drosophila melanogaster remains largely uncharacterized. We describe a novel protein, sisters on the loose (SOLO), which is essential for meiotic cohesion in Drosophila. In solo mutants, sister centromeres separate before prometaphase I, disrupting meiosis I centromere orientation and causing nondisjunction of both homologous and sister chromatids. Centromeric foci of the cohesin protein SMC1 are absent in solo mutants at all meiotic stages. SOLO and SMC1 colocalize to meiotic centromeres from early prophase I until anaphase II in wild-type males, but both proteins disappear prematurely at anaphase I in mutants for mei-S332, which encodes the Drosophila homologue of the cohesin protector protein shugoshin. The solo mutant phenotypes and the localization patterns of SOLO and SMC1 indicate that they function together to maintain sister chromatid cohesion in Drosophila meiosis.
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Lee, Janice Y., Aki Hayashi-Hagihara, and Terry L. Orr-Weaver. "Roles and regulation of the Drosophila centromere cohesion protein MEI-S332 family." Philosophical Transactions of the Royal Society B: Biological Sciences 360, no. 1455 (March 29, 2005): 543–52. http://dx.doi.org/10.1098/rstb.2005.1619.
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In meiosis, a physical attachment, or cohesion, between the centromeres of the sister chromatids is retained until their separation at anaphase II. This cohesion is essential for ensuring accurate segregation of the sister chromatids in meiosis II and avoiding aneuploidy, a condition that can lead to prenatal lethality or birth defects. The Drosophila MEI-S332 protein localizes to centromeres when sister chromatids are attached in mitosis and meiosis, and it is required to maintain cohesion at the centromeres after cohesion along the sister chromatid arms is lost at the metaphase I/anaphase I transition. MEI-S332 is the founding member of a family of proteins that protect centromeric cohesion but whose members also affect kinetochore behaviour and spindle microtubule dynamics. We compare the Drosophila MEI-S332 family members, evaluate the role of MEI-S332 in mitosis and meiosis I, and discuss the regulation of localization of MEI-S332 to the centromere and its dissociation at anaphase. We analyse the relationship between MEI-S332 and cohesin, a protein complex that is also necessary for sister-chromatid cohesion in mitosis and meiosis. In mitosis, centromere localization of MEI-S332 is not dependent upon the cohesin complex, and cohesin retains its association with mitotic chromosomes even in the absence of MEI-S332.
9
Jin, Hui, Vincent Guacci, and Hong-Guo Yu. "Pds5 is required for homologue pairing and inhibits synapsis of sister chromatids during yeast meiosis." Journal of Cell Biology 186, no. 5 (September 7, 2009): 713–25. http://dx.doi.org/10.1083/jcb.200810107.
Full textAbstract:
During meiosis, homologues become juxtaposed and synapsed along their entire length. Mutations in the cohesin complex disrupt not only sister chromatid cohesion but also homologue pairing and synaptonemal complex formation. In this study, we report that Pds5, a cohesin-associated protein known to regulate sister chromatid cohesion, is required for homologue pairing and synapsis in budding yeast. Pds5 colocalizes with cohesin along the length of meiotic chromosomes. In the absence of Pds5, the meiotic cohesin subunit Rec8 remains bound to chromosomes with only minor defects in sister chromatid cohesion, but sister chromatids synapse instead of homologues. Double-strand breaks (DSBs) are formed but are not repaired efficiently. In addition, meiotic chromosomes undergo hypercondensation. When the mitotic cohesin subunit Mcd1 is substituted for Rec8 in Pds5-depleted cells, chromosomes still hypercondense, but synapsis of sister chromatids is abolished. These data suggest that Pds5 modulates the Rec8 activity to facilitate chromosome morphological changes required for homologue synapsis, DSB repair, and meiotic chromosome segregation.
10
Boavida, Ana, Diana Santos, Mohammad Mahtab, and Francesca M. Pisani. "Functional Coupling between DNA Replication and Sister Chromatid Cohesion Establishment." International Journal of Molecular Sciences 22, no. 6 (March 10, 2021): 2810. http://dx.doi.org/10.3390/ijms22062810.
Full textAbstract:
Several lines of evidence suggest the existence in the eukaryotic cells of a tight, yet largely unexplored, connection between DNA replication and sister chromatid cohesion. Tethering of newly duplicated chromatids is mediated by cohesin, an evolutionarily conserved hetero-tetrameric protein complex that has a ring-like structure and is believed to encircle DNA. Cohesin is loaded onto chromatin in telophase/G1 and converted into a cohesive state during the subsequent S phase, a process known as cohesion establishment. Many studies have revealed that down-regulation of a number of DNA replication factors gives rise to chromosomal cohesion defects, suggesting that they play critical roles in cohesion establishment. Conversely, loss of cohesin subunits (and/or regulators) has been found to alter DNA replication fork dynamics. A critical step of the cohesion establishment process consists in cohesin acetylation, a modification accomplished by dedicated acetyltransferases that operate at the replication forks. Defects in cohesion establishment give rise to chromosome mis-segregation and aneuploidy, phenotypes frequently observed in pre-cancerous and cancerous cells. Herein, we will review our present knowledge of the molecular mechanisms underlying the functional link between DNA replication and cohesion establishment, a phenomenon that is unique to the eukaryotic organisms.
11
Revenkova, E., and R. Jessberger. "Keeping sister chromatids together: cohesins in meiosis." Reproduction 130, no. 6 (December 2005): 783–90. http://dx.doi.org/10.1530/rep.1.00864.
Full textAbstract:
Meiosis poses unique challenges to chromosome dynamics. Before entry into meiosis, each chromosome is duplicated and gives rise to two sister chromatids linked to each other by cohesion. Production of haploid gametes requires segregation of homologous chromosomes in the first meiotic division and of sister chromatids in the second. To ensure precise distribution of chromosomes to the daughter cells, sister chromatid cohesion (SCC) has to be dissolved in two steps. Maintenance and regulation of SCC is performed by the cohesin protein complex. This short review will primarily focus on the core cohesin proteins before venturing into adjacent territories with an emphasis on interacting proteins and complexes. It will also concentrate on mammalian meiosis and only occasionally discuss cohesion in other organisms.
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Finardi, Alice, Lucia F. Massari, and Rosella Visintin. "Anaphase Bridges: Not All Natural Fibers Are Healthy." Genes 11, no. 8 (August 7, 2020): 902. http://dx.doi.org/10.3390/genes11080902.
Full textAbstract:
At each round of cell division, the DNA must be correctly duplicated and distributed between the two daughter cells to maintain genome identity. In order to achieve proper chromosome replication and segregation, sister chromatids must be recognized as such and kept together until their separation. This process of cohesion is mainly achieved through proteinaceous linkages of cohesin complexes, which are loaded on the sister chromatids as they are generated during S phase. Cohesion between sister chromatids must be fully removed at anaphase to allow chromosome segregation. Other (non-proteinaceous) sources of cohesion between sister chromatids consist of DNA linkages or sister chromatid intertwines. DNA linkages are a natural consequence of DNA replication, but must be timely resolved before chromosome segregation to avoid the arising of DNA lesions and genome instability, a hallmark of cancer development. As complete resolution of sister chromatid intertwines only occurs during chromosome segregation, it is not clear whether DNA linkages that persist in mitosis are simply an unwanted leftover or whether they have a functional role. In this review, we provide an overview of DNA linkages between sister chromatids, from their origin to their resolution, and we discuss the consequences of a failure in their detection and processing and speculate on their potential role.
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Shi, Di, Shuaijun Zhao, Mei-Qing Zuo, Jingjing Zhang, Wenya Hou, Meng-Qiu Dong, Qinhong Cao, and Huiqiang Lou. "The acetyltransferase Eco1 elicits cohesin dimerization during S phase." Journal of Biological Chemistry 295, no. 22 (April 20, 2020): 7554–65. http://dx.doi.org/10.1074/jbc.ra120.013102.
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Cohesin is a DNA-associated protein complex that forms a tripartite ring controlling sister chromatid cohesion, chromosome segregation and organization, DNA replication, and gene expression. Sister chromatid cohesion is established by the protein acetyltransferase Eco1, which acetylates two conserved lysine residues on the cohesin subunit Smc3 and thereby ensures correct chromatid separation in yeast (Saccharomyces cerevisiae) and other eukaryotes. However, the consequence of Eco1-catalyzed cohesin acetylation is unknown, and the exact nature of the cohesive state of chromatids remains controversial. Here, we show that self-interactions of the cohesin subunits Scc1/Rad21 and Scc3 occur in a DNA replication–coupled manner in both yeast and human cells. Using cross-linking MS-based and in vivo disulfide cross-linking analyses of purified cohesin, we show that a subpopulation of cohesin may exist as dimers. Importantly, upon temperature-sensitive and auxin-induced degron-mediated Eco1 depletion, the cohesin-cohesin interactions became significantly compromised, whereas deleting either the deacetylase Hos1 or the Eco1 antagonist Wpl1/Rad61 increased cohesin dimer levels by ∼20%. These results indicate that cohesin dimerizes in the S phase and monomerizes in mitosis, processes that are controlled by Eco1, Wpl1, and Hos1 in the sister chromatid cohesion-dissolution cycle. These findings suggest that cohesin dimerization is controlled by the cohesion cycle and support the notion that a double-ring cohesin model operates in sister chromatid cohesion.
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Uchiyama, Susumu, and Kiichi Fukui. "Condensin in Chromatid Cohesion and Segregation." Cytogenetic and Genome Research 147, no. 4 (2015): 212–16. http://dx.doi.org/10.1159/000444868.
Full textAbstract:
After replication of genomic DNA during the S phase, 2 chromatids hold together longitudinally. When cells enter mitosis, the paired sister chromatids start to condense and then segregate into individual chromatids except for the centromeric region. Upon attachment of microtubules to the kinetochore, subsequent pulling of the 2 sister chromatids by the spindles towards opposite poles results in 2 completely separated chromatids. Besides more than 100 kinds of kinetochore proteins, several key proteins such as cohesin, separase, shugoshin, and condensin contribute to chromatid cohesion and segregation. Among these proteins, condensin, a protein complex composed of 5 subunits discovered 2 decades ago, has been extensively studied in terms of the maintenance of chromosome morphology as its major function. Recent studies on condensin uncovered its role in chromatid cohesion and segregation, which will be reviewed in this article.
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Nasmyth, Kim, and Alexander Schleiffer. "From a single double helix to paired double helices and back." Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences 359, no. 1441 (January 29, 2004): 99–108. http://dx.doi.org/10.1098/rstb.2003.1417.
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The propagation of our genomes during cell proliferation depends on the movement of sister DNA molecules produced by DNA replication to opposite sides of the cell before it divides. This feat is achieved by microtubules in eukaryotic cells but it has long remained a mystery how cells ensure that sister DNAs attach to microtubules with opposite orientations, known as amphitelic attachment. It is currently thought that sister chromatid cohesion has a crucial role. By resisting the forces exerted by microtubules, sister chromatid cohesion gives rise to tension that is thought essential for stabilizing kinetochore–microtubule attachments. Efficient amphitelic attachment is therefore achieved by an error correction mechanism that selectively eliminates connections that do not give rise to tension. Cohesion between sister chromatids is mediated by a multisubunit complex called cohesin which forms a gigantic ring structure. It has been proposed that sister DNAs are held together owing to their becoming entrapped within a single cohesin ring. Cohesion between sister chromatids is destroyed at the metaphase to anaphase transition by proteolytic cleavage of cohesin's Scc1 subunit by a thiol protease called separase, which severs the ring and thereby releases sister DNAs.
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Henrikus, Sarah S., and Alessandro Costa. "Towards a Structural Mechanism for Sister Chromatid Cohesion Establishment at the Eukaryotic Replication Fork." Biology 10, no. 6 (May 26, 2021): 466. http://dx.doi.org/10.3390/biology10060466.
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Cohesion between replicated chromosomes is essential for chromatin dynamics and equal segregation of duplicated genetic material. In the G1 phase, the ring-shaped cohesin complex is loaded onto duplex DNA, enriching at replication start sites, or “origins”. During the same phase of the cell cycle, and also at the origin sites, two MCM helicases are loaded as symmetric double hexamers around duplex DNA. During the S phase, and through the action of replication factors, cohesin switches from encircling one parental duplex DNA to topologically enclosing the two duplicated DNA filaments, which are known as sister chromatids. Despite its vital importance, the structural mechanism leading to sister chromatid cohesion establishment at the replication fork is mostly elusive. Here we review the current understanding of the molecular interactions between the replication machinery and cohesin, which support sister chromatid cohesion establishment and cohesin function. In particular, we discuss how cryo-EM is shedding light on the mechanisms of DNA replication and cohesin loading processes. We further expound how frontier cryo-EM approaches, combined with biochemistry and single-molecule fluorescence assays, can lead to understanding the molecular basis of sister chromatid cohesion establishment at the replication fork.
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Nakamura, Akito, Hiroyuki Arai, and Naoya Fujita. "Centrosomal Aki1 and cohesin function in separase-regulated centriole disengagement." Journal of Cell Biology 187, no. 5 (November 23, 2009): 607–14. http://dx.doi.org/10.1083/jcb.200906019.
Full textAbstract:
Sister chromatid separation at anaphase is triggered by cleavage of the cohesin subunit Scc1, which is mediated by separase. Centriole disengagement also requires separase. This dual role of separase permits concurrent control of these events for accurate metaphase to anaphase transition. Although the molecular mechanism underlying sister chromatid cohesion has been clarified, that of centriole cohesion is poorly understood. In this study, we show that Akt kinase–interacting protein 1 (Aki1) localizes to centrosomes and regulates centriole cohesion. Aki1 depletion causes formation of multipolar spindles accompanied by centriole splitting, which is separase dependent. We also show that cohesin subunits localize to centrosomes and that centrosomal Scc1 is cleaved by separase coincidentally with chromatin Scc1, suggesting a role of Scc1 as a connector of centrioles as well as sister chromatids. Interestingly, Scc1 depletion strongly induces centriole splitting. Furthermore, Aki1 interacts with cohesin in centrosomes, and this interaction is required for centriole cohesion. We demonstrate that centrosome-associated Aki1 and cohesin play pivotal roles in preventing premature cleavage in centriole cohesion.
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McNally, Karen P., Elizabeth A. Beath, Brennan M. Danlasky, Consuelo Barroso, Ting Gong, Wenzhe Li, Enrique Martinez-Perez, and Francis J. McNally. "Cohesin is required for meiotic spindle assembly independent of its role in cohesion in C. elegans." PLOS Genetics 18, no. 10 (October 24, 2022): e1010136. http://dx.doi.org/10.1371/journal.pgen.1010136.
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Accurate chromosome segregation requires a cohesin-mediated physical attachment between chromosomes that are to be segregated apart, and a bipolar spindle with microtubule plus ends emanating from exactly two poles toward the paired chromosomes. We asked whether the striking bipolar structure of C. elegans meiotic chromosomes is required for bipolarity of acentriolar female meiotic spindles by time-lapse imaging of mutants that lack cohesion between chromosomes. Both a spo-11 rec-8 coh-4 coh-3 quadruple mutant and a spo-11 rec-8 double mutant entered M phase with separated sister chromatids lacking any cohesion. However, the quadruple mutant formed an apolar spindle whereas the double mutant formed a bipolar spindle that segregated chromatids into two roughly equal masses. Residual non-cohesive COH-3/4-dependent cohesin on separated sister chromatids of the double mutant was sufficient to recruit haspin-dependent Aurora B kinase, which mediated bipolar spindle assembly in the apparent absence of chromosomal bipolarity. We hypothesized that cohesin-dependent Aurora B might activate or inhibit spindle assembly factors in a manner that would affect their localization on chromosomes and found that the chromosomal localization patterns of KLP-7 and CLS-2 correlated with Aurora B loading on chromosomes. These results demonstrate that cohesin is essential for spindle assembly and chromosome segregation independent of its role in sister chromatid cohesion.
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Chiroli, Elena, Valentina Rossio, Giovanna Lucchini, and Simonetta Piatti. "The budding yeast PP2ACdc55 protein phosphatase prevents the onset of anaphase in response to morphogenetic defects." Journal of Cell Biology 177, no. 4 (May 14, 2007): 599–611. http://dx.doi.org/10.1083/jcb.200609088.
Full textAbstract:
Faithful chromosome transmission requires establishment of sister chromatid cohesion during S phase, followed by its removal at anaphase onset. Sister chromatids are tethered together by cohesin, which is displaced from chromosomes through cleavage of its Mcd1 subunit by the separase protease. Separase is in turn inhibited, up to this moment, by securin. Budding yeast cells respond to morphogenetic defects by a transient arrest in G2 with high securin levels and unseparated chromatids. We show that neither securin elimination nor forced cohesin cleavage is sufficient for anaphase in these conditions, suggesting that other factors contribute to cohesion maintainance in G2. We find that the protein phosphatase PP2A bound to its regulatory subunit Cdc55 plays a key role in this process, uncovering a new function for PP2ACdc55 in controlling a noncanonical pathway of chromatid cohesion removal.
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Warren, Cheryl D., D. Mark Eckley, Marina S. Lee, Joseph S. Hanna, Adam Hughes, Brian Peyser, Chunfa Jie, Rafael Irizarry, and Forrest A. Spencer. "S-Phase Checkpoint Genes Safeguard High-Fidelity Sister Chromatid Cohesion." Molecular Biology of the Cell 15, no. 4 (April 2004): 1724–35. http://dx.doi.org/10.1091/mbc.e03-09-0637.
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Cohesion establishment and maintenance are carried out by proteins that modify the activity of Cohesin, an essential complex that holds sister chromatids together. Constituents of the replication fork, such as the DNA polymerase α-binding protein Ctf4, contribute to cohesion in ways that are poorly understood. To identify additional cohesion components, we analyzed a ctf4Δ synthetic lethal screen performed on microarrays. We focused on a subset of ctf4Δ-interacting genes with genetic instability of their own. Our analyses revealed that 17 previously studied genes are also necessary for the maintenance of robust association of sisters in metaphase. Among these were subunits of the MRX complex, which forms a molecular structure similar to Cohesin. Further investigation indicated that the MRX complex did not contribute to metaphase cohesion independent of Cohesin, although an additional role may be contributed by XRS2. In general, results from the screen indicated a sister chromatid cohesion role for a specific subset of genes that function in DNA replication and repair. This subset is particularly enriched for genes that support the S-phase checkpoint. We suggest that these genes promote and protect a chromatin environment conducive to robust cohesion.
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Alomer, Reem M., Eulália M. L. da Silva, Jingrong Chen, Katarzyna M. Piekarz, Katherine McDonald, Courtney G. Sansam, Christopher L. Sansam, and Susannah Rankin. "Esco1 and Esco2 regulate distinct cohesin functions during cell cycle progression." Proceedings of the National Academy of Sciences 114, no. 37 (August 28, 2017): 9906–11. http://dx.doi.org/10.1073/pnas.1708291114.
Full textAbstract:
Sister chromatids are tethered together by the cohesin complex from the time they are made until their separation at anaphase. The ability of cohesin to tether sister chromatids together depends on acetylation of its Smc3 subunit by members of the Eco1 family of cohesin acetyltransferases. Vertebrates express two orthologs of Eco1, called Esco1 and Esco2, both of which are capable of modifying Smc3, but their relative contributions to sister chromatid cohesion are unknown. We therefore set out to determine the precise contributions of Esco1 and Esco2 to cohesion in vertebrate cells. Here we show that cohesion establishment is critically dependent upon Esco2. Although most Smc3 acetylation is Esco1 dependent, inactivation of the ESCO1 gene has little effect on mitotic cohesion. The unique ability of Esco2 to promote cohesion is mediated by sequences in the N terminus of the protein. We propose that Esco1-dependent modification of Smc3 regulates almost exclusively the noncohesive activities of cohesin, such as DNA repair, transcriptional control, chromosome loop formation, and/or stabilization. Collectively, our data indicate that Esco1 and Esco2 contribute to distinct and separable activities of cohesin in vertebrate cells.
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Bender, Dawn, Eulália Maria Lima Da Silva, Jingrong Chen, Annelise Poss, Lauren Gawey, Zane Rulon, and Susannah Rankin. "Multivalent interaction of ESCO2 with the replication machinery is required for sister chromatid cohesion in vertebrates." Proceedings of the National Academy of Sciences 117, no. 2 (December 26, 2019): 1081–89. http://dx.doi.org/10.1073/pnas.1911936117.
Full textAbstract:
The tethering together of sister chromatids by the cohesin complex ensures their accurate alignment and segregation during cell division. In vertebrates, sister chromatid cohesion requires the activity of the ESCO2 acetyltransferase, which modifies the Smc3 subunit of cohesin. It was shown recently that ESCO2 promotes cohesion through interaction with the MCM replicative helicase. However, ESCO2 does not significantly colocalize with the MCM complex, suggesting there are additional interactions important for ESCO2 function. Here we show that ESCO2 is recruited to replication factories, sites of DNA replication, through interaction with PCNA. We show that ESCO2 contains multiple PCNA-interaction motifs in its N terminus, each of which is essential to its ability to establish cohesion. We propose that multiple PCNA-interaction motifs embedded in a largely flexible and disordered region of the protein underlie the unique ability of ESCO2 to establish cohesion between sister chromatids precisely as they are born during DNA replication.
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Suja, J. A., C. Antonio, A. Debec, and J. S. Rufas. "Phosphorylated proteins are involved in sister-chromatid arm cohesion during meiosis I." Journal of Cell Science 112, no. 17 (September 1, 1999): 2957–69. http://dx.doi.org/10.1242/jcs.112.17.2957.
Full textAbstract:
Sister-chromatid arm cohesion is lost during the metaphase I/anaphase I transition to allow homologue separation. To obtain needed information on this process we have analysed in grasshopper bivalents the sequential release of arm cohesion in relation to the behaviour of chromatid axes. Results show that sister axes are associated during early metaphase I but separate during late metaphase I leading to a concomitant change of chromosome structure that implies the loss of sister-kinetochore cohesion. Afterwards, homologues initiate their separation asynchronously depending on their size, and number and position of chiasmata. In all bivalents thin chromatin strands at the telomeres appeared as the last point of contact between sister chromatids. Additionally, we have analysed the participation of phosphoproteins recognised by the MPM-2 monoclonal antibody against mitotic phosphoproteins in arm cohesion in bivalents and two different kinds of univalents. Results show the absence of MPM-2 phosphoproteins at the interchromatid domain in mitotic chromosomes and meiotic univalents, but their presence in metaphase I bivalents. These phosphoproteins are lost at the onset of anaphase I. Taken together, these data have prompted us to propose a ‘working’ model for the release of arm cohesion during meiosis I. The model suggests that MPM-2 phosphoproteins may act as cohesive proteins associating sister axes. Their modification, once all bivalents are correctly aligned at the metaphase plate, would trigger a change of chromosome structure and the sequential release of sister-kinetochore, arm, and telomere cohesions.
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Morrison, C., P. Vagnarelli, E. Sonoda, S. Takeda, and W. C. Earnshaw. "Sister chromatid cohesion and genome stability in vertebrate cells." Biochemical Society Transactions 31, no. 1 (February 1, 2003): 263–65. http://dx.doi.org/10.1042/bst0310263.
Full textAbstract:
For successful eukaryotic mitosis, sister chromatid pairs remain linked after replication until their kinetochores have been attached to opposite spindle poles by microtubules. This linkage is broken at the metaphase–anaphase transition and the sisters separate. In budding yeast, this sister chromatid cohesion requires a multi-protein complex called cohesin. A key component of cohesin is Scc1/Mcd1 (Rad21 in fission yeast). Disruption of the chicken orthologue of Scc1 by gene targeting in DT40 cells causes premature sister chromatid separation. Cohesion between sister chromatids is likely to provide a substrate for post-replicative DNA repair by homologous recombination. In keeping with this role of cohesion, Scc1 mutants also show defects in the repair of spontaneous and induced DNA damage. Scc1-deficient cells frequently fail to complete metaphase chromosome alignment and show chromosome segregation defects, suggesting aberrant kinetochore function. Consistent with this, the chromosomal passenger protein, INCENP (inner centromere protein) fails to localize to centromeres. Survivin, another passenger protein and one which interacts with INCENP, also fails to localize to centromeres in Scc1-deficient cells. These results show that cohesin maintains genomic stability by ensuring appropriate DNA repair and equal chromosome segregation at mitosis.
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McNicoll, François, Anne Kühnel, Uddipta Biswas, Kai Hempel, Gabriela Whelan, Gregor Eichele, and Rolf Jessberger. "Meiotic sex chromosome cohesion and autosomal synapsis are supported by Esco2." Life Science Alliance 3, no. 3 (February 12, 2020): e201900564. http://dx.doi.org/10.26508/lsa.201900564.
Full textAbstract:
In mitotic cells, establishment of sister chromatid cohesion requires acetylation of the cohesin subunit SMC3 (acSMC3) by ESCO1 and/or ESCO2. Meiotic cohesin plays additional but poorly understood roles in the formation of chromosome axial elements (AEs) and synaptonemal complexes. Here, we show that levels of ESCO2, acSMC3, and the pro-cohesion factor sororin increase on meiotic chromosomes as homologs synapse. These proteins are less abundant on the largely unsynapsed sex chromosomes, whose sister chromatid cohesion appears weaker throughout the meiotic prophase. Using three distinct conditional Esco2 knockout mouse strains, we demonstrate that ESCO2 is essential for male gametogenesis. Partial depletion of ESCO2 in prophase I spermatocytes delays chromosome synapsis and further weakens cohesion along sex chromosomes, which show extensive separation of AEs into single chromatids. Unsynapsed regions of autosomes are associated with the sex chromatin and also display split AEs. This study provides the first evidence for a specific role of ESCO2 in mammalian meiosis, identifies a particular ESCO2 dependence of sex chromosome cohesion and suggests support of autosomal synapsis by acSMC3-stabilized cohesion.
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Eng, Thomas, Vincent Guacci, and Douglas Koshland. "Interallelic complementation provides functional evidence for cohesin–cohesin interactions on DNA." Molecular Biology of the Cell 26, no. 23 (November 15, 2015): 4224–35. http://dx.doi.org/10.1091/mbc.e15-06-0331.
Full textAbstract:
The cohesin complex (Mcd1p, Smc1p, Smc3p, and Scc3p) has multiple roles in chromosome architecture, such as promoting sister chromatid cohesion, chromosome condensation, DNA repair, and transcriptional regulation. The prevailing embrace model for sister chromatid cohesion posits that a single cohesin complex entraps both sister chromatids. We report interallelic complementation between pairs of nonfunctional mcd1 alleles (mcd1-1 and mcd1-Q266) or smc3 alleles (smc3-42 and smc3-K113R). Cells bearing individual mcd1 or smc3 mutant alleles are inviable and defective for both sister chromatid cohesion and condensation. However, cells coexpressing two defective mcd1 or two defective smc3 alleles are viable and have cohesion and condensation. Because cohesin contains only a single copy of Smc3p or Mcd1p, these examples of interallelic complementation must result from interplay or communication between the two defective cohesin complexes, each harboring one of the mutant allele products. Neither mcd1-1p nor smc3-42p is bound to chromosomes when expressed individually at its restrictive temperature. However, their chromosome binding is restored when they are coexpressed with their chromosome-bound interallelic complementing partner. Our results support a mechanism by which multiple cohesin complexes interact on DNA to mediate cohesion and condensation.
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Guacci, Vincent, and Douglas Koshland. "Cohesin-independent segregation of sister chromatids in budding yeast." Molecular Biology of the Cell 23, no. 4 (February 15, 2012): 729–39. http://dx.doi.org/10.1091/mbc.e11-08-0696.
Full textAbstract:
Cohesin generates cohesion between sister chromatids, which enables chromosomes to form bipolar attachments to the mitotic spindle and segregate. Cohesin also functions in chromosome condensation, transcriptional regulation, and DNA damage repair. Here we analyze the role of acetylation in modulating cohesin functions and how it affects budding yeast viability. Previous studies show that cohesion establishment requires Eco1p-mediated acetylation of the cohesin subunit Smc3p at residue K113. Smc3p acetylation was proposed to promote establishment by merely relieving Wpl1p inhibition because deletion of WPL1 bypasses the lethality of an ECO1 deletion (eco1Δ wpl1Δ). We find that little, if any, cohesion is established in eco1Δ wpl1Δ cells, indicating that Eco1p performs a function beyond antagonizing Wpl1p. Cohesion also fails to be established when SMC3 acetyl-mimics (K113Q or K112R,K113Q) are the sole functional SMC3s in cells. These results suggest that Smc3p acetylation levels affect establishment. It is remarkable that, despite their severe cohesion defect, eco1Δ wpl1Δ and smc3-K112R,K113Q strains are viable because a cohesin-independent mechanism enables bipolar attachment and segregation. This alternative mechanism is insufficient for smc3-K113Q strain viability. Smc3-K113Q is defective for condensation, whereas eco1Δ wpl1Δ and smc3-K112R,K113Q strains are competent for condensation. We suggest that Smc3p acetylation and Wpl1p antagonistically regulate cohesin's essential role in condensation.
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Canudas, Silvia, and Susan Smith. "Differential regulation of telomere and centromere cohesion by the Scc3 homologues SA1 and SA2, respectively, in human cells." Journal of Cell Biology 187, no. 2 (October 12, 2009): 165–73. http://dx.doi.org/10.1083/jcb.200903096.
Full textAbstract:
Replicated sister chromatids are held together until mitosis by cohesin, a conserved multisubunit complex comprised of Smc1, Smc3, Scc1, and Scc3, which in vertebrate cells exists as two closely related homologues (SA1 and SA2). Here, we show that cohesinSA1 and cohesinSA2 are differentially required for telomere and centromere cohesion, respectively. Cells deficient in SA1 are unable to establish or maintain cohesion between sister telomeres after DNA replication in S phase. The same phenotype is observed upon depletion of the telomeric protein TIN2. In contrast, in SA2-depleted cells telomere cohesion is normal, but centromere cohesion is prematurely lost. We demonstrate that loss of telomere cohesion has dramatic consequences on chromosome morphology and function. In the absence of sister telomere cohesion, cells are unable to repair chromatid breaks and suffer sister telomere loss. Our studies elucidate the functional distinction between the Scc3 homologues in human cells and further reveal an essential role for sister telomere cohesion in genomic integrity.
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Balicky, Eric M., Matthew W. Endres, Cary Lai, and Sharon E. Bickel. "Meiotic Cohesion Requires Accumulation of ORD on Chromosomes before Condensation." Molecular Biology of the Cell 13, no. 11 (November 2002): 3890–900. http://dx.doi.org/10.1091/mbc.e02-06-0332.
Full textAbstract:
Cohesion between sister chromatids is a prerequisite for accurate chromosome segregation during mitosis and meiosis. To allow chromosome condensation during prophase, the connections that hold sister chromatids together must be maintained but still permit extensive chromatin compaction. In Drosophila, null mutations in the orientation disruptor (ord) gene lead to meiotic nondisjunction in males and females because cohesion is absent by the time that sister kinetochores make stable microtubule attachments. We provide evidence that ORD is concentrated within the extrachromosomal domains of the nuclei ofDrosophila primary spermatocytes during early G2, but accumulates on the meiotic chromosomes by mid to late G2. Moreover, using fluorescence in situ hybridization to monitor cohesion directly, we show that cohesion defects first become detectable inord null spermatocytes shortly after the time when wild-type ORD associates with the chromosomes. After condensation, ORD remains bound at the centromeres of wild-type spermatocytes and persists there until centromeric cohesion is released during anaphase II. Our results suggest that association of ORD with meiotic chromosomes during mid to late G2 is required to maintain sister-chromatid cohesion during prophase condensation and that retention of ORD at the centromeres after condensation ensures the maintenance of centromeric cohesion until anaphase II.
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Nasmyth, Kim. "How might cohesin hold sister chromatids together?" Philosophical Transactions of the Royal Society B: Biological Sciences 360, no. 1455 (March 29, 2005): 483–96. http://dx.doi.org/10.1098/rstb.2004.1604.
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The sister chromatid cohesion essential for the bi-orientation of chromosomes on mitotic spindles depends on a multi-subunit complex called cohesin. This paper reviews the evidence that cohesin is directly responsible for holding sister DNAs together and considers how it might perform this function in the light of recent data on its structure.
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Kateneva, Anna V., Anton A. Konovchenko, Vincent Guacci, and Michael E. Dresser. "Recombination protein Tid1p controls resolution of cohesin-dependent linkages in meiosis in Saccharomyces cerevisiae." Journal of Cell Biology 171, no. 2 (October 17, 2005): 241–53. http://dx.doi.org/10.1083/jcb.200505020.
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Sister chromatid cohesion and interhomologue recombination are coordinated to promote the segregation of homologous chromosomes instead of sister chromatids at the first meiotic division. During meiotic prophase in Saccharomyces cerevisiae, the meiosis-specific cohesin Rec8p localizes along chromosome axes and mediates most of the cohesion. The mitotic cohesin Mcd1p/Scc1p localizes to discrete spots along chromosome arms, and its function is not clear. In cells lacking Tid1p, which is a member of the SWI2/SNF2 family of helicase-like proteins that are involved in chromatin remodeling, Mcd1p and Rec8p persist abnormally through both meiotic divisions, and chromosome segregation fails in the majority of cells. Genetic results indicate that the primary defect in these cells is a failure to resolve Mcd1p-mediated connections. Tid1p interacts with recombination enzymes Dmc1p and Rad51p and has an established role in recombination repair. We propose that Tid1p remodels Mcd1p-mediated cohesion early in meiotic prophase to facilitate interhomologue recombination and the subsequent segregation of homologous chromosomes.
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Galander, Stefan, Rachael E. Barton, David A. Kelly, and Adèle L. Marston. "Spo13 prevents premature cohesin cleavage during meiosis." Wellcome Open Research 4 (September 2, 2019): 29. http://dx.doi.org/10.12688/wellcomeopenres.15066.2.
Full textAbstract:
Background: Meiosis produces gametes through two successive nuclear divisions, meiosis I and meiosis II. In contrast to mitosis and meiosis II, where sister chromatids are segregated, during meiosis I, homologous chromosomes are segregated. This requires the monopolar attachment of sister kinetochores and the loss of cohesion from chromosome arms, but not centromeres, during meiosis I. The establishment of both sister kinetochore mono-orientation and cohesion protection rely on the budding yeast meiosis I-specific Spo13 protein, the functional homolog of fission yeast Moa1 and mouse MEIKIN. Methods: Here we investigate the effects of loss of SPO13 on cohesion during meiosis I using a live-cell imaging approach. Results: Unlike wild type, cells lacking SPO13 fail to maintain the meiosis-specific cohesin subunit, Rec8, at centromeres and segregate sister chromatids to opposite poles during anaphase I. We show that the cohesin-destabilizing factor, Wpl1, is not primarily responsible for the loss of cohesion during meiosis I. Instead, premature loss of centromeric cohesin during anaphase I in spo13Δ cells relies on separase-dependent cohesin cleavage. Further, cohesin loss in spo13Δ anaphase I cells is blocked by forcibly tethering the regulatory subunit of protein phosphatase 2A, Rts1, to Rec8. Conclusions: Our findings indicate that separase-dependent cleavage of phosphorylated Rec8 causes premature cohesin loss in spo13Δ cells.
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Lin, Weiqiang, Hui Jin, Xiuwen Liu, Kristin Hampton, and Hong-Guo Yu. "Scc2 regulates gene expression by recruiting cohesin to the chromosome as a transcriptional activator during yeast meiosis." Molecular Biology of the Cell 22, no. 12 (June 15, 2011): 1985–96. http://dx.doi.org/10.1091/mbc.e10-06-0545.
Full textAbstract:
To tether sister chromatids, a protein-loading complex, including Scc2, recruits cohesin to the chromosome at discrete loci. Cohesin facilitates the formation of a higher-order chromosome structure that could also influence gene expression. How cohesin directly regulates transcription remains to be further elucidated. We report that in budding yeast Scc2 is required for sister-chromatid cohesion during meiosis for two reasons. First, Scc2 is required for activating the expression of REC8, which encodes a meiosis-specific cohesin subunit; second, Scc2 is necessary for recruiting meiotic cohesin to the chromosome to generate sister-chromatid cohesion. Using a heterologous reporter assay, we have found that Scc2 increases the activity of its target promoters by recruiting cohesin to establish an upstream cohesin-associated region in a position-dependent manner. Rec8-associated meiotic cohesin is required for the full activation of the REC8 promoter, revealing that cohesin has a positive feedback on transcriptional regulation. Finally, we provide evidence that chromosomal binding of cohesin is sufficient for target-gene activation during meiosis. Our data support a noncanonical role for cohesin as a transcriptional activator during cell differentiation.
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Galander, Stefan, Rachael E. Barton, David A. Kelly, and Adèle L. Marston. "Spo13 prevents premature cohesin cleavage during meiosis." Wellcome Open Research 4 (February 13, 2019): 29. http://dx.doi.org/10.12688/wellcomeopenres.15066.1.
Full textAbstract:
Background: Meiosis produces gametes through two successive nuclear divisions, meiosis I and meiosis II. In contrast to mitosis and meiosis II, where sister chromatids are segregated, during meiosis I, homologous chromosomes are segregated. This requires the monopolar attachment of sister kinetochores and the loss of cohesion from chromosome arms, but not centromeres, during meiosis I. The establishment of both sister kinetochore mono-orientation and cohesin protection rely on the budding yeast meiosis I-specific Spo13 protein, the functional homolog of fission yeast Moa1 and mouse MEIKIN. Methods: Here we investigate the effects of loss of SPO13 on cohesion during meiosis I using a live-cell imaging approach. Results: Unlike wild type, cells lacking SPO13 fail to maintain the meiosis-specific cohesin subunit, Rec8, at centromeres and segregate sister chromatids to opposite poles during anaphase I. We show that the cohesin-destabilizing factor, Wpl1, is not primarily responsible for the loss of cohesion during meiosis I. Instead, premature loss of centromeric cohesin during anaphase I in spo13Δ cells relies on separase-dependent cohesin cleavage. Further, cohesin loss in spo13Δ anaphase I cells is blocked by forcibly tethering the regulatory subunit of protein phosphatase 2A, Rts1, to Rec8. Conclusions: Our findings indicate that separase-dependent cleavage of phosphorylated Rec8 causes premature cohesin loss in spo13Δ cells.
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Konecna, Marketa, Soodabeh Abbasi Sani, and Martin Anger. "Separase and Roads to Disengage Sister Chromatids during Anaphase." International Journal of Molecular Sciences 24, no. 5 (February 27, 2023): 4604. http://dx.doi.org/10.3390/ijms24054604.
Full textAbstract:
Receiving complete and undamaged genetic information is vital for the survival of daughter cells after chromosome segregation. The most critical steps in this process are accurate DNA replication during S phase and a faithful chromosome segregation during anaphase. Any errors in DNA replication or chromosome segregation have dire consequences, since cells arising after division might have either changed or incomplete genetic information. Accurate chromosome segregation during anaphase requires a protein complex called cohesin, which holds together sister chromatids. This complex unifies sister chromatids from their synthesis during S phase, until separation in anaphase. Upon entry into mitosis, the spindle apparatus is assembled, which eventually engages kinetochores of all chromosomes. Additionally, when kinetochores of sister chromatids assume amphitelic attachment to the spindle microtubules, cells are finally ready for the separation of sister chromatids. This is achieved by the enzymatic cleavage of cohesin subunits Scc1 or Rec8 by an enzyme called Separase. After cohesin cleavage, sister chromatids remain attached to the spindle apparatus and their poleward movement on the spindle is initiated. The removal of cohesion between sister chromatids is an irreversible step and therefore it must be synchronized with assembly of the spindle apparatus, since precocious separation of sister chromatids might lead into aneuploidy and tumorigenesis. In this review, we focus on recent discoveries concerning the regulation of Separase activity during the cell cycle.
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Miyazaki, W. Y., and T. L. Orr-Weaver. "Sister-chromatid misbehavior in Drosophila ord mutants." Genetics 132, no. 4 (December 1, 1992): 1047–61. http://dx.doi.org/10.1093/genetics/132.4.1047.
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Abstract In Drosophila males and females mutant for the ord gene, sister chromatids prematurely disjoin in meiosis. We have isolated five new alleles of ord and analyzed them both as homozygotes and in trans to deficiencies for the locus, and we show that ord function is necessary early in meiosis of both sexes. Strong ord alleles result in chromosome nondisjunction in meiosis I that appears to be the consequence of precocious separation of the sister chromatids followed by their random segregation. Cytological analysis in males confirmed that precocious disjunction of the sister chromatids occurs in prometaphase I. This is in contrast to Drosophila mei-S332 mutants, in which precocious sister-chromatid separation also occurs, but not until late in anaphase I. All three of the new female fertile ord alleles reduce recombination, suggesting they affect homolog association as well as sister-chromatid cohesion. In addition to the effect of ord mutations on meiosis, we find that in ord2 mutants chromosome segregation is aberrant in the mitotic divisions that produce the spermatocytes. The strongest ord alleles, ord2 and ord5, appear to cause defects in germline divisions in the female. These alleles are female sterile and produce egg chambers with altered nurse cell number, size, and nuclear morphology. In contrast to the effects of ord mutations on germline mitosis, all of the alleles are fully viable even when in trans to a deficiency, and thus exhibit no essential role in somatic mitosis. The ord gene product may prevent premature sister-chromatid separation by promoting cohesion of the sister chromatids in a structural or regulatory manner.
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Meadows, John C., and Jonathan B. A. Millar. "Sharpening the anaphase switch." Biochemical Society Transactions 43, no. 1 (January 26, 2015): 19–22. http://dx.doi.org/10.1042/bst20140250.
Full textAbstract:
The segregation of sister chromatids during mitosis is one of the most easily visualized, yet most remarkable, events during the life cycle of a cell. The accuracy of this process is essential to maintain ploidy during cell duplication. Over the past 20 years, substantial progress has been made in identifying components of both the kinetochore and the mitotic spindle that generate the force to move mitotic chromosomes. Additionally, we now have a reasonable, albeit incomplete, understanding of the molecular and biochemical events that are involved in establishing and dissolving sister-chromatid cohesion. However, it is less well-understood how this dissolution of cohesion occurs synchronously on all chromosomes at the onset of anaphase. At the centre of the action is the anaphase-promoting complex/cyclosome (APC/C), an E3 ubiquitin ligase that, in association with its activator cell-division cycle protein 20 homologue (Cdc20), is responsible for the destruction of securin. This leads to the activation of separase, a specialized protease that cleaves the kleisin-subunit of the cohesin complex, to relieve cohesion between sister chromatids. APC/C–Cdc20 is also responsible for the destruction of cyclin B and therefore inactivation of the cyclin B–cyclin-dependent kinase 1 (Cdk1). This latter event induces a change in the microtubule dynamics that results in the movement of sister chromatids to spindle poles (anaphase A), spindle elongation (anaphase B) and the onset of cytokinesis. In the present paper, we review the emerging evidence that multiple, spatially and temporally regulated feedback loops ensure anaphase onset is rapid, co-ordinated and irreversible.
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Zhang, Nenggang, Sergey G. Kuznetsov, Shyam K. Sharan, Kaiyi Li, Pulivarthi H. Rao, and Debananda Pati. "A handcuff model for the cohesin complex." Journal of Cell Biology 183, no. 6 (December 15, 2008): 1019–31. http://dx.doi.org/10.1083/jcb.200801157.
Full textAbstract:
The cohesin complex is responsible for the accurate separation of sister chromatids into two daughter cells. Several models for the cohesin complex have been proposed, but the one-ring embrace model currently predominates the field. However, the static configuration of the embrace model is not flexible enough for cohesins to perform their functions during DNA replication, transcription, and DNA repair. We used coimmunoprecipitation, a protein fragment complement assay, and a yeast two-hybrid assay to analyze the protein–protein interactions among cohesin subunits. The results show that three of the four human cohesin core subunits (Smc1, Smc3, and Rad21) interact with themselves in an Scc3 (SA1/SA2)-dependent manner. These data support a two-ring handcuff model for the cohesin complex, which is flexible enough to establish and maintain sister chromatid cohesion as well as ensure the fidelity of chromosome segregation in higher eukaryotes.
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Eijpe, Maureen, Hildo Offenberg, Rolf Jessberger, Ekaterina Revenkova, and Christa Heyting. "Meiotic cohesin REC8 marks the axial elements of rat synaptonemal complexes before cohesins SMC1β and SMC3." Journal of Cell Biology 160, no. 5 (March 3, 2003): 657–70. http://dx.doi.org/10.1083/jcb.200212080.
Full textAbstract:
In meiotic prophase, the sister chromatids of each chromosome develop a common axial element (AE) that is integrated into the synaptonemal complex (SC). We analyzed the incorporation of sister chromatid cohesion proteins (cohesins) and other AE components into AEs. Meiotic cohesin REC8 appeared shortly before premeiotic S phase in the nucleus and formed AE-like structures (REC8-AEs) from premeiotic S phase on. Subsequently, meiotic cohesin SMC1β, cohesin SMC3, and AE proteins SCP2 and SCP3 formed dots along REC8-AEs, which extended and fused until they lined REC8-AEs along their length. In metaphase I, SMC1β, SMC3, SCP2, and SCP3 disappeared from the chromosome arms and accumulated around the centromeres, where they stayed until anaphase II. In striking contrast, REC8 persisted along the chromosome arms until anaphase I and near the centromeres until anaphase II. We propose that REC8 provides a basis for AE formation and that the first steps in AE assembly do not require SMC1β, SMC3, SCP2, and SCP3. Furthermore, SMC1β, SMC3, SCP2, and SCP3 cannot provide arm cohesion during metaphase I. We propose that REC8 then provides cohesion. RAD51 and/or DMC1 coimmunoprecipitates with REC8, suggesting that REC8 may also provide a basis for assembly of recombination complexes.
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Landeira, David, Jean-Mathieu Bart, Daria Van Tyne, and Miguel Navarro. "Cohesin regulates VSG monoallelic expression in trypanosomes." Journal of Cell Biology 186, no. 2 (July 27, 2009): 243–54. http://dx.doi.org/10.1083/jcb.200902119.
Full textAbstract:
Antigenic variation allows Trypanosoma brucei to evade the host immune response by switching the expression of 1 out of ∼15 telomeric variant surface glycoprotein (VSG) expression sites (ESs). VSG ES transcription is mediated by RNA polymerase I in a discrete nuclear site named the ES body (ESB). However, nothing is known about how the monoallelic VSG ES transcriptional state is maintained over generations. In this study, we show that during S and G2 phases and early mitosis, the active VSG ES locus remains associated with the single ESB and exhibits a delay in the separation of sister chromatids relative to control loci. This delay is dependent on the cohesin complex, as partial knockdown of cohesin subunits resulted in premature separation of sister chromatids of the active VSG ES. Cohesin depletion also prompted transcriptional switching from the active to previously inactive VSG ESs. Thus, in addition to maintaining sister chromatid cohesion during mitosis, the cohesin complex plays an essential role in the correct epigenetic inheritance of the active transcriptional VSG ES state.
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Severin, Fedor, Anthony A. Hyman, and Simonetta Piatti. "Correct spindle elongation at the metaphase/anaphase transition is an APC-dependent event in budding yeast." Journal of Cell Biology 155, no. 5 (November 26, 2001): 711–18. http://dx.doi.org/10.1083/jcb.200104096.
Full textAbstract:
At the metaphase to anaphase transition, chromosome segregation is initiated by the splitting of sister chromatids. Subsequently, spindles elongate, separating the sister chromosomes into two sets. Here, we investigate the cell cycle requirements for spindle elongation in budding yeast using mutants affecting sister chromatid cohesion or DNA replication. We show that separation of sister chromatids is not sufficient for proper spindle integrity during elongation. Rather, successful spindle elongation and stability require both sister chromatid separation and anaphase-promoting complex activation. Spindle integrity during elongation is dependent on proteolysis of the securin Pds1 but not on the activity of the separase Esp1. Our data suggest that stabilization of the elongating spindle at the metaphase to anaphase transition involves Pds1-dependent targets other than Esp1.
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Rieder, C. L., and R. Cole. "Chromatid cohesion during mitosis: lessons from meiosis." Journal of Cell Science 112, no. 16 (August 15, 1999): 2607–13. http://dx.doi.org/10.1242/jcs.112.16.2607.
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The equal distribution of chromosomes during mitosis and meiosis is dependent on the maintenance of sister chromatid cohesion. In this commentary we review the evidence that, during meiosis, the mechanism underlying the cohesion of chromatids along their arms is different from that responsible for cohesion in the centromere region. We then argue that the chromatids on a mitotic chromosome are also tethered along their arms and in the centromere by different mechanisms, and that the functional action of these two mechanisms can be temporally separated under various conditions. Finally, we demonstrate that in the absence of a centromeric tether, arm cohesion is sufficient to maintain chromatid cohesion during prometaphase of mitosis. This finding provides a straightforward explanation for why mutants in proteins responsible for centromeric cohesion in Drosophila (e.g. ord, mei-s332) disrupt meiosis but not mitosis.
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Gartenberg, Marc. "Heterochromatin and the cohesion of sister chromatids." Chromosome Research 17, no. 2 (February 2009): 229–38. http://dx.doi.org/10.1007/s10577-008-9012-z.
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Kerrebrock, A. W., W. Y. Miyazaki, D. Birnby, and T. L. Orr-Weaver. "The Drosophila mei-S332 gene promotes sister-chromatid cohesion in meiosis following kinetochore differentiation." Genetics 130, no. 4 (April 1, 1992): 827–41. http://dx.doi.org/10.1093/genetics/130.4.827.
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Abstract The Drosophila mei-S332 gene acts to maintain sister-chromatid cohesion before anaphase II of meiosis in both males and females. By isolating and analyzing seven new alleles and a deficiency uncovering the mei-S332 gene we have demonstrated that the onset of the requirement for mei-S332 is not until late anaphase I. All of our alleles result primarily in equational (meiosis II) nondisjunction with low amounts of reductional (meiosis I) nondisjunction. Cytological analysis revealed that sister chromatids frequently separate in late anaphase I in these mutants. Since the sister chromatids remain associated until late in the first division, chromosomes segregate normally during meiosis I, and the genetic consequences of premature sister-chromatid dissociation are seen as nondisjunction in meiosis II. The late onset of mei-S332 action demonstrated by the mutations was not a consequence of residual gene function because two strong, and possibly null, alleles give predominantly equational nondisjunction both as homozygotes and in trans to a deficiency. mei-S332 is not required until after metaphase I, when the kinetochore differentiates from a single hemispherical kinetochore jointly organized by the sister chromatids into two distinct sister kinetochores. Therefore, we propose that the mei-S322 product acts to hold the doubled kinetochore together until anaphase II. All of the alleles are fully viable when in trans to a deficiency, thus mei-S332 is not essential for mitosis. Four of the alleles show an unexpected sex specificity.
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Rogers, Eric, John D. Bishop, James A. Waddle, Jill M. Schumacher, and Rueyling Lin. "The aurora kinase AIR-2 functions in the release of chromosome cohesion in Caenorhabditis elegans meiosis." Journal of Cell Biology 157, no. 2 (April 8, 2002): 219–29. http://dx.doi.org/10.1083/jcb.200110045.
Full textAbstract:
Accurate chromosome segregation during cell division requires not only the establishment, but also the precise, regulated release of chromosome cohesion. Chromosome dynamics during meiosis are more complicated, because homologues separate at anaphase I whereas sister chromatids remain attached until anaphase II. How the selective release of chromosome cohesion is regulated during meiosis remains unclear. We show that the aurora-B kinase AIR-2 regulates the selective release of chromosome cohesion during Caenorhabditis elegans meiosis. AIR-2 localizes to subchromosomal regions corresponding to last points of contact between homologues in metaphase I and between sister chromatids in metaphase II. Depletion of AIR-2 by RNA interference (RNAi) prevents chromosome separation at both anaphases, with concomitant prevention of meiotic cohesin REC-8 release from meiotic chromosomes. We show that AIR-2 phosphorylates REC-8 at a major amino acid in vitro. Interestingly, depletion of two PP1 phosphatases, CeGLC-7α and CeGLC-7β, abolishes the restricted localization pattern of AIR-2. In Ceglc-7α/β(RNAi) embryos, AIR-2 is detected on the entire bivalent. Concurrently, chromosomal REC-8 is dramatically reduced and sister chromatids are separated precociously at anaphase I in Ceglc-7α/β(RNAi) embryos. We propose that AIR-2 promotes the release of chromosome cohesion via phosphorylation of REC-8 at specific chromosomal locations and that CeGLC-7α/β, directly or indirectly, antagonize AIR-2 activity.
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Pinto, Belinda S., and Terry L. Orr-Weaver. "Drosophila protein phosphatases 2A B′ Wdb and Wrd regulate meiotic centromere localization and function of the MEI-S332 Shugoshin." Proceedings of the National Academy of Sciences 114, no. 49 (November 20, 2017): 12988–93. http://dx.doi.org/10.1073/pnas.1718450114.
Full textAbstract:
Proper segregation of chromosomes in meiosis is essential to prevent miscarriages and birth defects. This requires that sister chromatids maintain cohesion at the centromere as cohesion is released on the chromatid arms when the homologs segregate at anaphase I. The Shugoshin proteins preserve centromere cohesion by protecting the cohesin complex from cleavage, and this has been shown in yeasts to be mediated by recruitment of the protein phosphatase 2A B′ (PP2A B′). In metazoans, delineation of the role of PP2A B′ in meiosis has been hindered by its myriad of other essential roles. The Drosophila Shugoshin MEI-S332 can bind directly to both of the B′ regulatory subunits of PP2A, Wdb and Wrd, in yeast two-hybrid experiments. Exploiting experimental advantages of Drosophila spermatogenesis, we found that the Wdb subunit localizes first along chromosomes in meiosis I, becoming restricted to the centromere region as MEI-S332 binds. Wdb and MEI-S332 show colocalization at the centromere region until release of sister-chromatid cohesion at the metaphase II/anaphase II transition. MEI-S332 is necessary for Wdb localization, but, additionally, both Wdb and Wrd are required for MEI-S332 localization. Thus, rather than MEI-S332 being hierarchical to PP2A B′, these proteins reciprocally ensure centromere localization of the complex. We analyzed functional relationships between MEI-S332 and the two forms of PP2A by quantifying meiotic chromosome segregation defects in double or triple mutants. These studies revealed that both Wdb and Wrd contribute to MEI-S332’s ability to ensure accurate segregation of sister chromatids, but, as in centromere localization, they do not act solely downstream of MEI-S332.
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Hsiao, Susan J., and Susan Smith. "Sister telomeres rendered dysfunctional by persistent cohesion are fused by NHEJ." Journal of Cell Biology 184, no. 4 (February 16, 2009): 515–26. http://dx.doi.org/10.1083/jcb.200810132.
Full textAbstract:
Telomeres protect chromosome ends from being viewed as double-strand breaks and from eliciting a DNA damage response. Deprotection of chromosome ends occurs when telomeres become critically short because of replicative attrition or inhibition of TRF2. In this study, we report a novel form of deprotection that occurs exclusively after DNA replication in S/G2 phase of the cell cycle. In cells deficient in the telomeric poly(adenosine diphosphate ribose) polymerase tankyrase 1, sister telomere resolution is blocked. Unexpectedly, cohered sister telomeres become deprotected and are inappropriately fused. In contrast to telomeres rendered dysfunctional by TRF2, which engage in chromatid fusions predominantly between chromatids from different chromosomes (Bailey, S.M., M.N. Cornforth, A. Kurimasa, D.J. Chen, and E.H. Goodwin. 2001. Science. 293:2462–2465; Smogorzewska, A., J. Karlseder, H. Holtgreve-Grez, A. Jauch, and T. de Lange. 2002. Curr. Biol. 12:1635–1644), telomeres rendered dysfunctional by tankyrase 1 engage in chromatid fusions almost exclusively between sister chromatids. We show that cohered sister telomeres are fused by DNA ligase IV–mediated nonhomologous end joining. These results demonstrate that the timely removal of sister telomere cohesion is essential for the formation of a protective structure at chromosome ends after DNA replication in S/G2 phase of the cell cycle.
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Sumara, Izabela, Elisabeth Vorlaufer, Christian Gieffers, Beate H. Peters, and Jan-Michael Peters. "Characterization of Vertebrate Cohesin Complexes and Their Regulation in Prophase." Journal of Cell Biology 151, no. 4 (November 13, 2000): 749–62. http://dx.doi.org/10.1083/jcb.151.4.749.
Full textAbstract:
In eukaryotes, sister chromatids remain connected from the time of their synthesis until they are separated in anaphase. This cohesion depends on a complex of proteins called cohesins. In budding yeast, the anaphase-promoting complex (APC) pathway initiates anaphase by removing cohesins from chromosomes. In vertebrates, cohesins dissociate from chromosomes already in prophase. To study their mitotic regulation we have purified two 14S cohesin complexes from human cells. Both complexes contain SMC1, SMC3, SCC1, and either one of the yeast Scc3p orthologs SA1 and SA2. SA1 is also a subunit of 14S cohesin in Xenopus. These complexes interact with PDS5, a protein whose fungal orthologs have been implicated in chromosome cohesion, condensation, and recombination. The bulk of SA1- and SA2-containing complexes and PDS5 are chromatin-associated until they become soluble from prophase to telophase. Reconstitution of this process in mitotic Xenopus extracts shows that cohesin dissociation does neither depend on cyclin B proteolysis nor on the presence of the APC. Cohesins can also dissociate from chromatin in the absence of cyclin-dependent kinase 1 activity. These results suggest that vertebrate cohesins are regulated by a novel prophase pathway which is distinct from the APC pathway that controls cohesins in yeast.
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Rankin, Susannah, and Dean S. Dawson. "Recent advances in cohesin biology." F1000Research 5 (August 3, 2016): 1909. http://dx.doi.org/10.12688/f1000research.8881.1.
Full textAbstract:
Sister chromatids are tethered together from the time they are formed in S-phase until they separate at anaphase. A protein complex called cohesin is responsible for holding the sister chromatids together and serves important roles in chromosome condensation, gene regulation, and the repair of DNA damage. Cohesin contains an open central pore and becomes topologically engaged with its DNA substrates. Entrapped DNA can be released either by the opening of a gate in the cohesin ring or by proteolytic cleavage of a component of the ring. This review summarizes recent research that provides important new insights into how DNA enters and exits the cohesin ring and how the rings behave on entrapped DNA molecules to provide functional cohesion.
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Donnellan, Leigh, Clifford Young, Bradley S. Simpson, Varinderpal S. Dhillon, Maurizio Costabile, Peter Hoffmann, Michael Fenech, and Permal Deo. "Methylglyoxal Impairs Sister Chromatid Separation in Lymphocytes." International Journal of Molecular Sciences 23, no. 8 (April 8, 2022): 4139. http://dx.doi.org/10.3390/ijms23084139.
Full textAbstract:
The accurate segregation of sister chromatids is complex, and errors that arise throughout this process can drive chromosomal instability and tumorigenesis. We recently showed that methylglyoxal (MGO), a glycolytic by-product, can cause chromosome missegregation events in lymphocytes. However, the underlying mechanisms of this were not explored. Therefore, in this study, we utilised shotgun proteomics to identify MGO-modified proteins, and label-free quantitation to measure changes in protein abundance following exposure to MGO. We identified numerous mitotic proteins that were modified by MGO, including those involved in the separation and cohesion of sister chromatids. Furthermore, the protein abundance of Securin, an inhibitor of sister chromatid separation, was increased following treatment with MGO. Cytological examination of chromosome spreads showed MGO prevented sister chromatid separation, which was associated with the formation of complex nuclear anomalies. Therefore, results from this study suggest MGO may drive chromosomal instability by preventing sister chromatid separation.