scholarly journals Interallelic complementation provides functional evidence for cohesin–cohesin interactions on DNA

2015 ◽  
Vol 26 (23) ◽  
pp. 4224-4235 ◽  
Author(s):  
Thomas Eng ◽  
Vincent Guacci ◽  
Douglas Koshland
Keyword(s):  
Sister Chromatid ◽  
Single Copy ◽  
Sister Chromatid Cohesion ◽  
Multiple Roles ◽  
Restrictive Temperature ◽  
Cohesin Complex ◽  
Chromosome Architecture ◽  
Sister Chromatids ◽  
Chromatid Cohesion ◽  
Interallelic Complementation

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.

scholarly journals A conserved activity for cohesin in bridging DNA molecules

2019 ◽  
Author(s):  
Pilar Gutierrez-Escribano ◽  
Matthew D. Newton ◽  
Aida Llauró ◽  
Jonas Huber ◽  
Loredana Tanasie ◽  
...  
Keyword(s):  
Single Molecule ◽  
Sister Chromatid ◽  
Regulation Of Gene Expression ◽  
Sister Chromatid Cohesion ◽  
Dna Molecules ◽  
Chromosome Architecture ◽  
Physiological Conditions ◽  
Sister Chromatids ◽  
Chromatid Cohesion ◽  
Core Activity

AbstractEssential processes such as accurate chromosome segregation, regulation of gene expression and DNA repair rely on protein-mediated DNA tethering. Sister chromatid cohesion requires the SMC complex cohesin to act as a protein linker that holds replicated chromatids together (1, 2). The molecular mechanism by which cohesins hold sister chromatids has remained controversial. Here, we used a single molecule approach to visualise the activity of cohesin complexes as they hold DNA molecules. We describe a DNA bridging activity that requires ATP and is conserved from yeast to human cohesin. We show that cohesin can form two distinct classes of bridges at physiological conditions, a “permanent bridge” able to resists high force (over 80pN) and a “reversible bridge” that breaks at lower forces (5-40pN). Both classes of bridges require Scc2/Scc4 in addition to ATP. We demonstrate that bridge formation requires physical proximity of the DNA segments to be tethered and show that “permanent” cohesin bridges can move between two DNA molecules but cannot be removed from DNA when they occur in cis. This suggests that separate physical compartments in cohesin molecules are involved in the bridge. Finally, we show that cohesin tetramers, unlike condensin, cannot compact linear DNA molecules against low force, demonstrating that the core activity of cohesin tetramers is bridging DNA rather than compacting it. Our findings carry important implications for the understanding of the basic mechanisms behind cohesin-dependent establishment of sister chromatid cohesion and chromosome architecture.

scholarly journals SOLO: a meiotic protein required for centromere cohesion, coorientation, and SMC1 localization in Drosophila melanogaster

2010 ◽  
Vol 188 (3) ◽  
pp. 335-349 ◽  
Author(s):  
Rihui Yan ◽  
Sharon E. Thomas ◽  
Jui-He Tsai ◽  
Yukihiro Yamada ◽  
Bruce D. McKee
Keyword(s):  
Drosophila Melanogaster ◽  
Sister Chromatid ◽  
Sister Chromatid Cohesion ◽  
Early Prophase ◽  
Wild Type ◽  
Sister Chromatids ◽  
Chromatid Cohesion ◽  
Mutant Phenotypes ◽  
Meiosis I ◽  
Novel Protein

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.

scholarly journals Absence of the Spindle Assembly Checkpoint restores mitotic fidelity upon loss of sister chromatid cohesion

2018 ◽  
Author(s):  
Rui D. Silva ◽  
Mihailo Mirkovic ◽  
Leonardo G. Guilgur ◽  
Om S. Rathore ◽  
Rui Gonçalo Martinho ◽  
...  
Keyword(s):  
Cell Survival ◽  
Sister Chromatid ◽  
Spindle Assembly Checkpoint ◽  
Genome Shuffling ◽  
Spindle Assembly ◽  
Sister Chromatid Cohesion ◽  
Abnormal Development ◽  
Wing Development ◽  
Cohesin Complex ◽  
Chromatid Cohesion

AbstractSister chromatid cohesion is essential for faithful mitosis, as premature cohesion loss leads to random chromosome segregation and aneuploidy, resulting in abnormal development. To identify specific conditions capable of restoring defects associated with cohesion loss, we screened for genes whose depletion modulates Drosophila wing development when sister chromatid cohesion is impaired. Cohesion deficiency was induced by knock-down of the acetyltransferase Separation anxiety (San)/Naa50, a cohesin complex stabilizer. Several genes whose function impacts wing development upon cohesion loss were identified. Surprisingly, knockdown of key Spindle Assembly Checkpoint (SAC) proteins, Mad2 and Mps1, suppressed developmental defects associated with San depletion. SAC impairment upon cohesin removal, triggered by San depletion or artificial removal of the cohesin complex, prevented extensive genome shuffling, reduced segregation defects and restored cell survival. This counterintuitive phenotypic suppression was caused by an intrinsic bias for efficient chromosome bi-orientation at mitotic entry, coupled with slow engagement of error-correction reactions. We conclude that mitotic timing determines the severity of defects associated with cohesion deficiency. Therefore, although divisions are still error-prone, SAC inactivation enhances cell survival and tissue homeostasis upon cohesion loss.

scholarly journals Scc2/Nipbl hops between chromosomal cohesin rings after loading

2017 ◽  
Author(s):  
James D.P. Rhodes ◽  
Davide Mazza ◽  
Kim A. Nasmyth ◽  
Stephan Uphoff
Keyword(s):  
Single Molecule ◽  
Sister Chromatid ◽  
Fluorescence Recovery After Photobleaching ◽  
Sister Chromatid Cohesion ◽  
Dna Looping ◽  
Cohesin Complex ◽  
Single Molecule Tracking ◽  
Loading Function ◽  
Stop And Go ◽  
Chromatid Cohesion

AbstractThe cohesin complex mediates DNA-DNA interactions both between (sister chromatid cohesion) and within chromosomes (DNA looping) via a process thought to involve entrapment of DNAs within its tripartite ring. It has been suggested that intra- chromosome loops are generated through processive extrusion of DNAs through the lumen of cohesin’s ring. Scc2 (Nipbl) is essential for loading cohesin onto chromosomes but not for maintaining sister chromatid cohesion following DNA replication. It has therefore been assumed that Scc2 is involved exclusively in the cohesin loading process. However, it is possible that the stimulation of cohesin’s ABC-like ATPase by Scc2 also has a post-loading function, for example driving loop extrusion. Using fluorescence recovery after photobleaching (FRAP) and single-molecule tracking, we show that Scc2 binds dynamically to chromatin, principally through an association with cohesin. Scc2’s movement within chromatin is consistent with a “stop-and-go” or “hopping” motion. We suggest that a low diffusion coefficient, a low stoichiometry relative to cohesin, and a high affinity for chromosomal cohesin enables Scc2 to move rapidly from one chromosomal cohesin complex to another, performing a function distinct from loading.

Organization of Chromosomal DNA by SMC Complexes

2019 ◽  
Vol 53 (1) ◽  
pp. 445-482 ◽  
Author(s):  
Stanislau Yatskevich ◽  
James Rhodes ◽  
Kim Nasmyth
Keyword(s):  
Chromosome Segregation ◽  
Sister Chromatid ◽  
Mitotic Chromosome ◽  
Sister Chromatid Cohesion ◽  
Chromosomal Dna ◽  
Chromosome Architecture ◽  
Chromatid Cohesion ◽  
Dna Translocases ◽  
Structural Maintenance Of Chromosomes

Structural maintenance of chromosomes (SMC) complexes are key organizers of chromosome architecture in all kingdoms of life. Despite seemingly divergent functions, such as chromosome segregation, chromosome maintenance, sister chromatid cohesion, and mitotic chromosome compaction, it appears that these complexes function via highly conserved mechanisms and that they represent a novel class of DNA translocases.

scholarly journals Chromosome interaction over a distance in meiosis

2015 ◽  
Vol 2 (2) ◽  
pp. 150029 ◽  
Author(s):  
Mary Brady ◽  
Leocadia V. Paliulis
Keyword(s):  
Cell Division ◽  
Sex Chromosomes ◽  
Sister Chromatid ◽  
Daughter Cell ◽  
Sister Chromatid Cohesion ◽  
Sister Chromatids ◽  
Physical Connection ◽  
Chromatid Cohesion ◽  
Different Types ◽  
Random Segregation

The challenge of cell division is to distribute partner chromosomes (pairs of homologues, pairs of sex chromosomes or pairs of sister chromatids) correctly, one into each daughter cell. In the ‘standard’ meiosis, this problem is solved by linking partners together via a chiasma and/or sister chromatid cohesion, and then separating the linked partners from one another in anaphase; thus, the partners are kept track of, and correctly distributed. Many organisms, however, properly separate chromosomes in the absence of any obvious physical connection, and movements of unconnected partner chromosomes are coordinated at a distance. Meiotic distance interactions happen in many different ways and in different types of organisms. In this review, we discuss several different known types of distance segregation and propose possible explanations for non-random segregation of distance-segregating chromosomes.

scholarly journals The Multiple Roles of Cohesin in Meiotic Chromosome Morphogenesis and Pairing

2009 ◽  
Vol 20 (3) ◽  
pp. 1030-1047 ◽  
Author(s):  
Gloria A. Brar ◽  
Andreas Hochwagen ◽  
Ly-sha S. Ee ◽  
Angelika Amon
Keyword(s):  
Sister Chromatid ◽  
Meiotic Prophase ◽  
Meiotic Chromosome ◽  
Sister Chromatid Cohesion ◽  
Multiple Roles ◽  
Axis Formation ◽  
Chromatid Cohesion ◽  
Cohesin Subunit ◽  
Chromosome Axis ◽  
Segregation Of Chromosomes

Sister chromatid cohesion, mediated by cohesin complexes, is laid down during DNA replication and is essential for the accurate segregation of chromosomes. Previous studies indicated that, in addition to their cohesion function, cohesins are essential for completion of recombination, pairing, meiotic chromosome axis formation, and assembly of the synaptonemal complex (SC). Using mutants in the cohesin subunit Rec8, in which phosphorylated residues were mutated to alanines, we show that cohesin phosphorylation is not only important for cohesin removal, but that cohesin's meiotic prophase functions are distinct from each other. We find pairing and SC formation to be dependent on Rec8, but independent of the presence of a sister chromatid and hence sister chromatid cohesion. We identified mutations in REC8 that differentially affect Rec8's cohesion, pairing, recombination, chromosome axis and SC assembly function. These findings define Rec8 as a key determinant of meiotic chromosome morphogenesis and a central player in multiple meiotic events.

scholarly journals Pds5p regulates the maintenance of sister chromatid cohesion and is sumoylated to promote the dissolution of cohesion

2003 ◽  
Vol 163 (4) ◽  
pp. 729-741 ◽  
Author(s):  
Kristen Stead ◽  
Cristina Aguilar ◽  
Theresa Hartman ◽  
Melissa Drexel ◽  
Pamela Meluh ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Temperature Sensitivity ◽  
Sister Chromatid ◽  
Sister Chromatid Cohesion ◽  
Cohesin Complex ◽  
Chromatid Cohesion ◽  
Chromosomal Loci

Pds5p and the cohesin complex are required for sister chromatid cohesion and localize to the same chromosomal loci over the same cell cycle window. However, Pds5p and the cohesin complex likely have distinct roles in cohesion. We report that pds5 mutants establish cohesion, but during mitosis exhibit precocious sister dissociation. Thus, unlike the cohesin complex, which is required for cohesion establishment and maintenance, Pds5p is required only for maintenance. We identified SMT4, which encodes a SUMO isopeptidase, as a high copy suppressor of both the temperature sensitivity and precocious sister dissociation of pds5 mutants. In contrast, SMT4 does not suppress temperature sensitivity of cohesin complex mutants. Pds5p is SUMO conjugated, with sumoylation peaking during mitosis. SMT4 overexpression reduces Pds5p sumoylation, whereas smt4 mutants have increased Pds5p sumoylation. smt4 mutants were previously shown to be defective in cohesion maintenance during mitosis. These data provide the first link between a protein required for cohesion, Pds5p, and sumoylation, and suggest that Pds5p sumoylation promotes the dissolution of cohesion.

scholarly journals Hardwired synthetic lethality within the cohesin complex in human cancer cells

2017 ◽  
Author(s):  
Petra van der Lelij ◽  
Simone Lieb ◽  
Julian Jude ◽  
Gordana Wutz ◽  
Catarina P. Santos ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Cancer Cells ◽  
Sister Chromatid ◽  
Sister Chromatid Cohesion ◽  
Cohesin Complex ◽  
Wild Type ◽  
Synthetic Lethal ◽  
Recurrent Mutations ◽  
Wide Range ◽  
Chromatid Cohesion

AbstractRecent genome analyses have identified recurrent mutations in the cohesin complex in a wide range of human cancers. Here we demonstrate that the most frequently mutated subunit of the cohesin complex, STAG2, displays a strong synthetic lethal interaction with its paralog STAG1. Mechanistically, STAG1 loss abrogates sister chromatid cohesion in STAG2 mutated but not in wild-type cells leading to mitotic catastrophe, defective cell division and apoptosis. STAG1 inactivation inhibits the proliferation of STAG2 mutated but not wild-type bladder cancer and Ewing sarcoma cell lines. Restoration of STAG2 expression in a mutated bladder cancer model alleviates the dependency on STAG1. Thus, STAG1 and STAG2 act redundantly to support sister chromatid cohesion and cell survival. STAG1 represents a hardwired, context independent vulnerability of cancer cells carrying mutations in the major emerging tumor suppressor STAG2. Exploiting synthetic lethal interactions to target recurrent cohesin mutations in cancer, e.g. by inhibiting STAG1, holds the promise for the development of selective therapeutics.

scholarly journals Synthetic lethality between the cohesin subunits STAG1 and STAG2 in diverse cancer contexts

2017 ◽  
Author(s):  
Petra van der Lelij ◽  
Simone Lieb ◽  
Julian Jude ◽  
Gordana Wutz ◽  
Catarina P. Santos ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Sister Chromatid ◽  
Synthetic Lethality ◽  
Sister Chromatid Cohesion ◽  
Cohesin Complex ◽  
Wild Type ◽  
Synthetic Lethal ◽  
Recurrent Mutations ◽  
Wide Range ◽  
Chromatid Cohesion

AbstractRecent genome analyses have identified recurrent mutations in the cohesin complex in a wide range of human cancers. Here we demonstrate that the most frequently mutated subunit of the cohesin complex, STAG2, displays a strong synthetic lethal interaction with its paralog STAG1. Mechanistically, STAG1 loss abrogates sister chromatid cohesion in STAG2 mutated but not in wild-type cells leading to mitotic catastrophe, defective cell division and apoptosis. STAG1 inactivation inhibits the proliferation of STAG2 mutated but not wild-type bladder cancer and Ewing sarcoma cell lines. Restoration of STAG2 expression in a mutated bladder cancer model alleviates the dependency on STAG1. Thus, STAG1 and STAG2 support sister chromatid cohesion to redundantly ensure cell survival. STAG1 represents a vulnerability of cancer cells carrying mutations in the major emerging tumor suppressor STAG2 across different cancer contexts. Exploiting synthetic lethal interactions to target recurrent cohesin mutations in cancer, e.g. by inhibiting STAG1, holds the promise for the development of selective therapeutics.

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