scholarly journals Spindle checkpoint–independent inhibition of mitotic chromosome segregation byDrosophilaMps1

2012 ◽  
Vol 23 (12) ◽  
pp. 2275-2291 ◽  
Author(s):  
Friederike Althoff ◽  
Roger E. Karess ◽  
Christian F. Lehner
Keyword(s):  
Chromosome Segregation ◽  
Sister Chromatid ◽  
Spindle Assembly Checkpoint ◽  
Mitotic Chromosome ◽  
Independent Manner ◽  
Spindle Poles ◽  
Anaphase Onset ◽  
Chromosome Congression ◽  
Monopolar Spindle ◽  
Chromatid Cohesion

Monopolar spindle 1 (Mps1) is essential for the spindle assembly checkpoint (SAC), which prevents anaphase onset in the presence of misaligned chromosomes. Moreover, Mps1 kinase contributes in a SAC-independent manner to the correction of erroneous initial attachments of chromosomes to the spindle. Our characterization of the Drosophila homologue reveals yet another SAC-independent role. As in yeast, modest overexpression of Drosophila Mps1 is sufficient to delay progression through mitosis during metaphase, even though chromosome congression and metaphase alignment do not appear to be affected. This delay in metaphase depends on the SAC component Mad2. Although Mps1 overexpression in mad2 mutants no longer causes a metaphase delay, it perturbs anaphase. Sister kinetochores barely move apart toward spindle poles. However, kinetochore movements can be restored experimentally by separase-independent resolution of sister chromatid cohesion. We propose therefore that Mps1 inhibits sister chromatid separation in a SAC-independent manner. Moreover, we report unexpected results concerning the requirement of Mps1 dimerization and kinase activity for its kinetochore localization in Drosophila. These findings further expand Mps1's significance for faithful mitotic chromosome segregation and emphasize the importance of its careful regulation.

scholarly journals ConnectingGCN5’s centromeric SAGA to the mitotic tension-sensing checkpoint

2018 ◽  
Vol 29 (18) ◽  
pp. 2201-2212 ◽  
Author(s):  
Emily L. Petty ◽  
Masha Evpak ◽  
Lorraine Pillus
Keyword(s):  
Chromosome Segregation ◽  
Sister Chromatid ◽  
Spindle Assembly Checkpoint ◽  
Binding Function ◽  
Chromatid Cohesion ◽  
Histone H3 Variant ◽  
Spindle Microtubules ◽  
Low Tension ◽  
Centromere Histone H3 ◽  
Segregation Of Chromosomes

Multiple interdependent mechanisms ensure faithful segregation of chromosomes during cell division. Among these, the spindle assembly checkpoint monitors attachment of spindle microtubules to the centromere of each chromosome, whereas the tension-sensing checkpoint monitors the opposing forces between sister chromatid centromeres for proper biorientation. We report here a new function for the deeply conserved Gcn5 acetyltransferase in the centromeric localization of Rts1, a key player in the tension-sensing checkpoint. Rts1 is a regulatory component of protein phopshatase 2A, a near universal phosphatase complex, which is recruited to centromeres by the Shugoshin (Sgo) checkpoint component under low-tension conditions to maintain sister chromatid cohesion. We report that loss of Gcn5 disrupts centromeric localization of Rts1. Increased RTS1 dosage robustly suppresses gcn5∆ cell cycle and chromosome segregation defects, including restoration of Rts1 to centromeres. Sgo1’s Rts1-binding function also plays a key role in RTS1 dosage suppression of gcn5∆ phenotypes. Notably, we have identified residues of the centromere histone H3 variant Cse4 that function in these chromosome segregation-related roles of RTS1. Together, these findings expand the understanding of the mechanistic roles of Gcn5 and Cse4 in chromosome segregation.

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 Cohesins Determine the Attachment Manner of Kinetochores to Spindle Microtubules at Meiosis I in Fission Yeast

2003 ◽  
Vol 23 (11) ◽  
pp. 3965-3973 ◽  
Author(s):  
Shihori Yokobayashi ◽  
Masayuki Yamamoto ◽  
Yoshinori Watanabe
Keyword(s):  
Fission Yeast ◽  
Chromosome Segregation ◽  
Sister Chromatid ◽  
Specific Requirement ◽  
Spindle Poles ◽  
Chromatid Cohesion ◽  
Spindle Microtubules ◽  
Yeast Meiosis ◽  
Meiosis I ◽  
Random Division

ABSTRACT During mitosis, sister kinetochores attach to microtubules that extend to opposite spindle poles (bipolar attachment) and pull the chromatids apart at anaphase (equational segregation). A multisubunit complex called cohesin, including Rad21/Scc1, plays a crucial role in sister chromatid cohesion and equational segregation at mitosis. Meiosis I differs from mitosis in having a reductional pattern of chromosome segregation, in which sister kinetochores are attached to the same spindle (monopolar attachment). During meiosis, Rad21/Scc1 is largely replaced by its meiotic counterpart, Rec8. If Rec8 is inactivated in fission yeast, meiosis I is shifted from reductional to equational division. However, the reason rec8Δ cells undergo equational rather than random division has not been clarified; therefore, it has been unclear whether equational segregation is due to a loss of cohesin in general or to a loss of a specific requirement for Rec8. We report here that the equational segregation at meiosis I depends on substitutive Rad21, which relocates to the centromeres if Rec8 is absent. Moreover, we demonstrate that even if sufficient amounts of Rad21 are transferred to the centromeres at meiosis I, thereby establishing cohesion at the centromeres, rec8Δ cells never recover monopolar attachment but instead secure bipolar attachment. Thus, Rec8 and Rad21 define monopolar and bipolar attachment, respectively, at meiosis I. We conclude that cohesin is a crucial determinant of the attachment manner of kinetochores to the spindle microtubules at meiosis I in fission yeast.

scholarly journals Human kinetochores are swivel joints that mediate microtubule attachments

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Chris A Smith ◽  
Andrew D McAinsh ◽  
Nigel J Burroughs
Keyword(s):  
Chromosome Segregation ◽  
Sister Chromatid ◽  
Mitotic Spindle ◽  
Three Dimensional ◽  
Organisational Change ◽  
Mechanical Process ◽  
Spindle Poles ◽  
Chromatid Cohesion ◽  
Sister Kinetochore ◽  
Dynamic Microtubule

Chromosome segregation is a mechanical process that requires assembly of the mitotic spindle – a dynamic microtubule-based force-generating machine. Connections to this spindle are mediated by sister kinetochore pairs, that form dynamic end-on attachments to microtubules emanating from opposite spindle poles. This bi-orientation generates forces that have been reported to stretch the kinetochore itself, which has been suggested to stabilise attachment and silence the spindle checkpoint. We reveal using three dimensional tracking that the outer kinetochore domain can swivel around the inner kinetochore/centromere, which results in large reductions in intra-kinetochore distance (delta) when viewed in lower dimensions. We show that swivel provides a mechanical flexibility that enables kinetochores at the periphery of the spindle to engage microtubules. Swivel reduces as cells approach anaphase, suggesting an organisational change linked to checkpoint satisfaction and/or obligatory changes in kinetochore mechanochemistry may occur before dissolution of sister chromatid cohesion.

scholarly journals BUB-1 promotes amphitelic chromosome biorientation via multiple activities at the kinetochore

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Frances Edwards ◽  
Gilliane Maton ◽  
Nelly Gareil ◽  
Julie C Canman ◽  
Julien Dumont
Keyword(s):  
Chromosome Segregation ◽  
Spindle Assembly Checkpoint ◽  
Underlying Mechanism ◽  
Microtubule Assembly ◽  
Spindle Poles ◽  
Microtubule Attachment ◽  
Anaphase Onset ◽  
Chromatid Segregation ◽  
Associated Proteins ◽  
Chromosome Attachment

Accurate chromosome segregation relies on bioriented amphitelic attachments of chromosomes to microtubules of the mitotic spindle, in which sister chromatids are connected to opposite spindle poles. BUB-1 is a protein of the Spindle Assembly Checkpoint (SAC) that coordinates chromosome attachment with anaphase onset. BUB-1 is also required for accurate sister chromatid segregation independently of its SAC function, but the underlying mechanism remains unclear. Here we show that, in Caenorhabditis elegans embryos, BUB-1 accelerates the establishment of non-merotelic end-on kinetochore-microtubule attachments by recruiting the RZZ complex and its downstream partner dynein-dynactin at the kinetochore. In parallel, BUB-1 limits attachment maturation by the SKA complex. This activity opposes kinetochore-microtubule attachment stabilisation promoted by CLS-2CLASP-dependent kinetochore-microtubule assembly. BUB-1 is therefore a SAC component that coordinates the function of multiple downstream kinetochore-associated proteins to ensure accurate chromosome segregation.

Sister chromatid cohesion and genome stability in vertebrate cells

2003 ◽  
Vol 31 (1) ◽  
pp. 263-265 ◽  
Author(s):  
C. Morrison ◽  
P. Vagnarelli ◽  
E. Sonoda ◽  
S. Takeda ◽  
W.C. Earnshaw
Keyword(s):  
Dna Repair ◽  
Chromosome Segregation ◽  
Sister Chromatid ◽  
Genome Stability ◽  
Sister Chromatid Cohesion ◽  
Spindle Poles ◽  
Chromatid Cohesion ◽  
Chromosomal Passenger ◽  
Passenger Protein

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.

scholarly journals SENP1 and SENP2 affect spatial and temporal control of sumoylation in mitosis

2013 ◽  
Vol 24 (22) ◽  
pp. 3483-3495 ◽  
Author(s):  
Caelin Cubeñas-Potts ◽  
Jacqueline D. Goeres ◽  
Michael J. Matunis
Keyword(s):  
Rna Interference ◽  
Chromosome Segregation ◽  
Nuclear Pore Complex ◽  
Sister Chromatid ◽  
Mitotic Chromosome ◽  
Nuclear Pore ◽  
Temporal Control ◽  
Chromosome Congression ◽  
Associated Proteins ◽  
Sister Chromatid Separation

Sumoylation of centromere, kinetochore, and other mitotic chromosome-associated proteins is essential for chromosome segregation. The mechanisms regulating spatial and temporal sumoylation of proteins in mitosis, however, are not well understood. Here we show that the small ubiquitin-related modifier (SUMO)–specific isopeptidases SENP1 and SENP2 are targeted to kinetochores in mitosis. SENP2 targeting occurs through a mechanism dependent on the Nup107-160 subcomplex of the nuclear pore complex and is modulated through interactions with karyopherin α. Overexpression of SENP2, but not other SUMO-specific isopeptidases, causes a defect in chromosome congression that depends on its precise kinetochore targeting. By altering SENP1 kinetochore associations, however, this effect on chromosome congression could be phenocopied. In contrast, RNA interference–mediated knockdown of SENP1 delays sister chromatid separation at metaphase, whereas SENP2 knockdown produces no detectable phenotypes. Our findings indicate that chromosome segregation depends on precise spatial and temporal control of sumoylation in mitosis and that SENP1 and SENP2 are important mediators of this control.

The checkpoint control for anaphase onset does not monitor excess numbers of spindle poles or bipolar spindle symmetry

1997 ◽  
Vol 110 (4) ◽  
pp. 421-429 ◽  
Author(s):  
G. Sluder ◽  
E.A. Thompson ◽  
F.J. Miller ◽  
J. Hayes ◽  
C.L. Rieder
Keyword(s):  
Sea Urchin ◽  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Microtubule Assembly ◽  
Checkpoint Control ◽  
Animal Cells ◽  
Bipolar Spindle ◽  
Spindle Poles ◽  
Anaphase Onset ◽  
Monopolar Spindle

Exit from mitosis in animal cells is substantially delayed when spindle assembly is inhibited, spindle bipolarity is disrupted, or when a monopolar spindle is formed. These observations have led to the proposal that animal cells have a ‘spindle assembly’ checkpoint for the metaphase-anaphase transition that monitors bipolar spindle organization. However, the existence of such a checkpoint is uncertain because perturbations in spindle organization can produce unattached kinetochores, which by themselves are known to delay anaphase onset. In this study we have tested if cells monitor bipolar spindle organization, independent of kinetochore attachment, by analyzing the duration of mitosis in sea urchin zygotes and vertebrate somatic cells containing multipolar spindles in which all kinetochores are attached to spindle poles. We found that sea urchin zygotes containing tripolar or tetrapolar spindles progressed from nuclear envelope breakdown to anaphase onset with normal timing. We also found that the presence of supernumerary, unpaired spindle poles did not greatly prolong mitosis. Observation of untreated PtK1 cells that formed tripolar or tetrapolar spindles revealed that they progressed through mitosis, on average, at the normal rate. More importantly, the interval between the bipolar attachment of the last monooriented chromosome and anaphase onset was normal. Thus, neither of these cell types can detect the presence of gross aberrations in spindle architecture that inevitably lead to aneuploidy. We conclude that animal cells do not have a checkpoint for the metaphase-anaphase transition that monitors defects in spindle architecture independent of the checkpoint that monitors kinetochore attachment to the spindle. For dividing cells in which spindle microtubule assembly is not experimentally compromised, we propose that the completion of kinetochore attachment is the event which limits the time of the metaphase-anaphase transition.

scholarly journals Recent advances in understanding the role of Cdk1 in the Spindle Assembly Checkpoint

F1000Research ◽  
2020 ◽  
Vol 9 ◽  
pp. 57 ◽  
Author(s):  
Angela Flavia Serpico ◽  
Domenico Grieco
Keyword(s):  
Mitotic Spindle ◽  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Daughter Cells ◽  
Spindle Poles ◽  
Anaphase Onset ◽  
Sister Chromatids ◽  
Chromatid Cohesion ◽  
M Phase ◽  
Safeguard Mechanism

The goal of mitosis is to form two daughter cells each containing one copy of each mother cell chromosome, replicated in the previous S phase. To achieve this, sister chromatids held together back-to-back at their primary constriction, the centromere, have to interact with microtubules of the mitotic spindle so that each chromatid takes connections with microtubules emanating from opposite spindle poles (we will refer to this condition as bipolar attachment). Only once all replicated chromosomes have reached bipolar attachments can sister chromatids lose cohesion with each other, at the onset of anaphase, and move toward opposite spindle poles, being segregated into what will soon become the daughter cell nucleus. Prevention of errors in chromosome segregation is granted by a safeguard mechanism called Spindle Assembly Checkpoint (SAC). Until all chromosomes are bipolarly oriented at the equator of the mitotic spindle, the SAC prevents loss of sister chromatid cohesion, thus anaphase onset, and maintains the mitotic state by inhibiting inactivation of the major M phase promoting kinase, the cyclin B-cdk1 complex (Cdk1). Here, we review recent mechanistic insights about the circuitry that links Cdk1 to the SAC to ensure correct achievement of the goal of mitosis.

scholarly journals Multiple Subunits of the Caenorhabditis elegans Anaphase-Promoting Complex Are Required for Chromosome Segregation During Meiosis I

Genetics ◽  
2002 ◽  
Vol 160 (2) ◽  
pp. 805-813 ◽  
Author(s):  
Edward S Davis ◽  
Lucia Wille ◽  
Barry A Chestnut ◽  
Penny L Sadler ◽  
Diane C Shakes ◽  
...  
Keyword(s):  
Rna Interference ◽  
Caenorhabditis Elegans ◽  
Chromosome Segregation ◽  
Sister Chromatid ◽  
Sister Chromatid Cohesion ◽  
Anaphase Promoting Complex ◽  
Genetic Screens ◽  
Chromatid Cohesion ◽  
Interference Studies ◽  
Meiosis I

Abstract Two genes, originally identified in genetic screens for Caenorhabditis elegans mutants that arrest in metaphase of meiosis I, prove to encode subunits of the anaphase-promoting complex or cyclosome (APC/C). RNA interference studies reveal that these and other APC/C subunits are essential for the segregation of chromosomal homologs during meiosis I. Further, chromosome segregation during meiosis I requires APC/C functions in addition to the release of sister chromatid cohesion.

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