scholarly journals CDK1-mediated phosphorylation at H2B serine 6 is required for mitotic chromosome segregation

2019 ◽  
Vol 218 (4) ◽  
pp. 1164-1181 ◽  
Author(s):  
Markus Seibert ◽  
Marcus Krüger ◽  
Nikolaus A. Watson ◽  
Onur Sen ◽  
John R. Daum ◽  
...  
Keyword(s):  
Chromosome Segregation ◽  
Chromosomal Instability ◽  
Mitotic Chromosome ◽  
Chromatin Modification ◽  
Genomic Stability ◽  
Cyclin B1 ◽  
Aurora B ◽  
Chromatin Binding ◽  
Histone H2b ◽  
Chromosome Separation

Faithful mitotic chromosome segregation is required for the maintenance of genomic stability. We discovered the phosphorylation of histone H2B at serine 6 (H2B S6ph) as a new chromatin modification site and found that this modification occurs during the early mitotic phases at inner centromeres and pericentromeric heterochromatin. This modification is directly mediated by cyclin B1–associated CDK1, and indirectly by Aurora B, and is antagonized by PP1-mediated dephosphorylation. H2B S6ph impairs chromatin binding of the histone chaperone SET (I2PP2A), which is important for mitotic fidelity. Injection of phosphorylation-specific H2B S6 antibodies in mitotic cells caused anaphase defects with impaired chromosome segregation and incomplete cytokinesis. As H2B S6ph is important for faithful chromosome separation, this modification may contribute to the prevention chromosomal instability and aneuploidy which frequently occur in cancer cells.

scholarly journals Differential requirement for Bub1 and Bub3 in regulation of meiotic versus mitotic chromosome segregation

2020 ◽  
Vol 219 (4) ◽  
Author(s):  
Gisela Cairo ◽  
Anne M. MacKenzie ◽  
Soni Lacefield
Keyword(s):  
Chromosome Segregation ◽  
Protein Phosphatase ◽  
Mitotic Chromosome ◽  
Budding Yeast ◽  
Meiotic Chromosome ◽  
Protein Phosphatase 1 ◽  
Aurora B ◽  
Chromosome Missegregation ◽  
Anaphase Onset ◽  
Spindle Microtubules

Accurate chromosome segregation depends on the proper attachment of kinetochores to spindle microtubules before anaphase onset. The Ipl1/Aurora B kinase corrects improper attachments by phosphorylating kinetochore components and so releasing aberrant kinetochore–microtubule interactions. The localization of Ipl1 to kinetochores in budding yeast depends upon multiple pathways, including the Bub1–Bub3 pathway. We show here that in meiosis, Bub3 is crucial for correction of attachment errors. Depletion of Bub3 results in reduced levels of kinetochore-localized Ipl1 and concomitant massive chromosome missegregation caused by incorrect chromosome–spindle attachments. Depletion of Bub3 also results in shorter metaphase I and metaphase II due to premature localization of protein phosphatase 1 (PP1) to kinetochores, which antagonizes Ipl1-mediated phosphorylation. We propose a new role for the Bub1–Bub3 pathway in maintaining the balance between kinetochore localization of Ipl1 and PP1, a balance that is essential for accurate meiotic chromosome segregation and timely anaphase onset.

scholarly journals Aurora B kinase activity is regulated by SET/TAF1 on Sgo2 at the inner centromere

2019 ◽  
Vol 218 (10) ◽  
pp. 3223-3236 ◽  
Author(s):  
Yuichiro Asai ◽  
Koh Fukuchi ◽  
Yuji Tanno ◽  
Saki Koitabashi-Kiyozuka ◽  
Tatsuyuki Kiyozuka ◽  
...  
Keyword(s):  
Chromosome Segregation ◽  
Chromosomal Instability ◽  
Kinase Activity ◽  
Fine Tuning ◽  
Aurora B ◽  
The Novel ◽  
Aurora B Kinase ◽  
Microtubule Attachment ◽  
Molecular Events

The accurate regulation of phosphorylation at the kinetochore is essential for establishing chromosome bi-orientation. Phosphorylation of kinetochore proteins by the Aurora B kinase destabilizes improper kinetochore–microtubule attachments, whereas the phosphatase PP2A has a counteracting role. Imbalanced phosphoregulation leads to error-prone chromosome segregation and aneuploidy, a hallmark of cancer cells. However, little is known about the molecular events that control the balance of phosphorylation at the kinetochore. Here, we show that localization of SET/TAF1, an oncogene product, to centromeres maintains Aurora B kinase activity by inhibiting PP2A, thereby correcting erroneous kinetochore–microtubule attachment. SET localizes at the inner centromere by interacting directly with shugoshin 2, with SET levels declining at increased distances between kinetochore pairs, leading to establishment of chromosome bi-orientation. Moreover, SET overexpression induces chromosomal instability by disrupting kinetochore–microtubule attachment. Thus, our findings reveal the novel role of SET in fine-tuning the phosphorylation level at the kinetochore by balancing the activities of Aurora B and PP2A.

scholarly journals The aurora kinase AIR-2 functions in the release of chromosome cohesion in Caenorhabditis elegans meiosis

2002 ◽  
Vol 157 (2) ◽  
pp. 219-229 ◽  
Author(s):  
Eric Rogers ◽  
John D. Bishop ◽  
James A. Waddle ◽  
Jill M. Schumacher ◽  
Rueyling Lin
Keyword(s):  
Caenorhabditis Elegans ◽  
Chromosome Segregation ◽  
Aurora Kinase ◽  
Aurora B ◽  
Localization Pattern ◽  
Meiotic Chromosomes ◽  
Sister Chromatids ◽  
Chromosome Separation ◽  
Major Amino Acid

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.

scholarly journals Spatiotemporal control of mitotic exit during anaphase by an aurora B-Cdk1 crosstalk

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Olga Afonso ◽  
Colleen M Castellani ◽  
Liam P Cheeseman ◽  
Jorge G Ferreira ◽  
Bernardo Orr ◽  
...  
Keyword(s):  
Spindle Assembly Checkpoint ◽  
Cyclin B1 ◽  
Mitotic Exit ◽  
Aurora B ◽  
Dependent Manner ◽  
Slowing Down ◽  
Molecular Rulers ◽  
Spindle Midzone ◽  
Chromosome Separation ◽  
Chromosome Motion

According to the prevailing ‘clock’ model, chromosome decondensation and nuclear envelope reformation when cells exit mitosis are byproducts of Cdk1 inactivation at the metaphase-anaphase transition, controlled by the spindle assembly checkpoint. However, mitotic exit was recently shown to be a function of chromosome separation during anaphase, assisted by a midzone Aurora B phosphorylation gradient - the ‘ruler’ model. Here we found that Cdk1 remains active during anaphase due to ongoing APC/CCdc20- and APC/CCdh1-mediated degradation of B-type Cyclins in Drosophila and human cells. Failure to degrade B-type Cyclins during anaphase prevented mitotic exit in a Cdk1-dependent manner. Cyclin B1-Cdk1 localized at the spindle midzone in an Aurora B-dependent manner, with incompletely separated chromosomes showing the highest Cdk1 activity. Slowing down anaphase chromosome motion delayed Cyclin B1 degradation and mitotic exit in an Aurora B-dependent manner. Thus, a crosstalk between molecular ‘rulers’ and ‘clocks’ licenses mitotic exit only after proper chromosome separation.

scholarly journals Phosphorylation of CENP-C by Aurora B facilitates kinetochore attachment error correction in mitosis

2017 ◽  
Vol 114 (50) ◽  
pp. E10667-E10676 ◽  
Author(s):  
Xing Zhou ◽  
Fan Zheng ◽  
Chengliang Wang ◽  
Minhao Wu ◽  
Xiaozhen Zhang ◽  
...  
Keyword(s):  
Error Correction ◽  
Chromosome Segregation ◽  
Spindle Assembly Checkpoint ◽  
Mitotic Chromosome ◽  
Regulatory Mechanism ◽  
Dynamic Interaction ◽  
Aurora B ◽  
Kinetochore Assembly ◽  
Important Pathway ◽  
Spindle Microtubules

Kinetochores are superprotein complexes that orchestrate chromosome segregation via a dynamic interaction with spindle microtubules. A physical connection between CENP-C and the Mis12–Ndc80–Knl1 (KMN) protein network is an important pathway that is used to assemble kinetochores on CENP-A nucleosomes. Multiple outer kinetochore components are phosphorylated by Aurora B kinase to activate the spindle assembly checkpoint (SAC) and to ensure accurate chromosome segregation. However, it is unknown whether Aurora B can phosphorylate inner kinetochore components to facilitate proper mitotic chromosome segregation. Here, we reported the structure of the fission yeast Schizosaccharomyces pombe Mis12–Nnf1 complex and showed that N-terminal residues 26–50 in Cnp3 (the CENP-C homolog of S. pombe) are responsible for interacting with the Mis12 complex. Interestingly, Thr28 of Cnp3 is a substrate of Ark1 (the Aurora B homolog of S. pombe), and phosphorylation impairs the interaction between the Cnp3 and Mis12 complex. The expression of a phosphorylation-mimicking Cnp3 mutant results in defective chromosome segregation due to improper kinetochore assembly. These results establish a previously uncharacterized regulatory mechanism involved in CENP-C–Mis12-facilitated kinetochore attachment error correction to ensure accurate chromosome segregation during mitosis.

scholarly journals Prophase removal of chromosome-associated RNAs facilitates anaphase chromosome segregation

2019 ◽  
Author(s):  
Judith A. Sharp ◽  
Wei Wang ◽  
Michael D. Blower
Keyword(s):  
Cell Division ◽  
Chromosome Segregation ◽  
Mitotic Chromosome ◽  
Nuclear Protein ◽  
Aurora B ◽  
Dna Binding Domain ◽  
Nucleic Acid Binding ◽  
Mitotic Chromosomes ◽  
Nuclear Envelope Breakdown ◽  
Binding Domains

AbstractDuring mitosis, the genome is transformed from a decondensed, transcriptionally active state to a highly condensed, transcriptionally inactive state. Mitotic chromosome reorganization is marked by the general attenuation of transcription on chromosome arms, yet how the cell regulates nuclear and chromatin-associated RNAs after chromosome condensation and nuclear envelope breakdown is unknown. SAF-A/hnRNPU is an abundant nuclear protein with RNA-to-DNA tethering activity, coordinated by two spatially distinct nucleic acid binding domains. Here we show that RNA is evicted from prophase chromosomes through Aurora-B-dependent phosphorylation of the SAF-A DNA-binding domain; failure to execute this pathway leads to accumulation of SAF-A:RNA complexes on mitotic chromosomes and elevated rates of anaphase segregation defects. This work reveals a role for Aurora-B in removing chromatin-associated RNAs during prophase, and demonstrates that Aurora-B dependent relocalization of SAF-A during cell division contributes to the fidelity of chromosome segregation.

scholarly journals Regulated targeting of protein phosphatase 1 to the outer kinetochore by KNL1 opposes Aurora B kinase

2010 ◽  
Vol 188 (6) ◽  
pp. 809-820 ◽  
Author(s):  
Dan Liu ◽  
Mathijs Vleugel ◽  
Chelsea B. Backer ◽  
Tetsuya Hori ◽  
Tatsuo Fukagawa ◽  
...  
Keyword(s):  
Chromosome Segregation ◽  
Protein Phosphatase ◽  
Genomic Stability ◽  
Feedback Mechanism ◽  
Protein Phosphatase 1 ◽  
Aurora B ◽  
Aurora B Kinase ◽  
Conserved Motif ◽  
Spindle Microtubules ◽  
Positive Feedback Mechanism

Regulated interactions between kinetochores and spindle microtubules are essential to maintain genomic stability during chromosome segregation. The Aurora B kinase phosphorylates kinetochore substrates to destabilize kinetochore–microtubule interactions and eliminate incorrect attachments. These substrates must be dephosphorylated to stabilize correct attachments, but how opposing kinase and phosphatase activities are coordinated at the kinetochore is unknown. Here, we demonstrate that a conserved motif in the kinetochore protein KNL1 directly interacts with and targets protein phosphatase 1 (PP1) to the outer kinetochore. PP1 recruitment by KNL1 is required to dephosphorylate Aurora B substrates at kinetochores and stabilize microtubule attachments. PP1 levels at kinetochores are regulated and inversely proportional to local Aurora B activity. Indeed, we demonstrate that phosphorylation of KNL1 by Aurora B disrupts the KNL1–PP1 interaction. In total, our results support a positive feedback mechanism by which Aurora B activity at kinetochores not only targets substrates directly, but also prevents localization of the opposing phosphatase.

scholarly journals Mitotic exit is controlled during anaphase by an Aurora B-Cyclin B1/Cdk1 crosstalk

2019 ◽  
Author(s):  
Olga Afonso ◽  
Liam P. Cheeseman ◽  
Luísa T. Ferreira ◽  
Eurico Morais-de-Sá ◽  
Helder Maiato
Keyword(s):  
Spindle Assembly Checkpoint ◽  
Cyclin B1 ◽  
Mitotic Exit ◽  
Aurora B ◽  
Dependent Manner ◽  
Clock Model ◽  
Molecular Rulers ◽  
Spindle Midzone ◽  
Chromosome Separation ◽  
Chromosome Decondensation

SummaryAccording to the prevailing “clock” model, chromosome decondensation and nuclear envelope reassembly during mitotic exit are byproducts of Cdk1 inactivation at the metaphase-anaphase transition, controlled by the spindle assembly checkpoint. However, mitotic exit was recently shown to be a function of chromosome separation during anaphase, assisted by a midzone Aurora B phosphorylation gradient - the “ruler” model. Here we reconciled both models by showing that Cyclin B1 degradation continues during anaphase inDrosophila, mouse and human cells, including primary tissues. This required APC/CCdh1activity, and failure to degrade Cyclin B1 during anaphase prevented mitotic exit in a Cdk1-dependent manner. Cyclin B1 localization and half-life during anaphase depended on kinesin-6, which targets Aurora B to the spindle midzone. Mechanistically, we show that anaphase duration is regulated by Aurora B-mediated phosphorylation of Cyclin B1. We propose that a crosstalk between molecular “rulers” and “clocks” licenses mitotic exit only after proper chromosome separation.

scholarly journals Cell division requires RNA eviction from condensing chromosomes

2020 ◽  
Vol 219 (11) ◽  
Author(s):  
Judith A. Sharp ◽  
Carlos Perea-Resa ◽  
Wei Wang ◽  
Michael D. Blower
Keyword(s):  
Cell Division ◽  
Chromosome Segregation ◽  
Mitotic Chromosome ◽  
Aurora B ◽  
Nucleic Acid Binding ◽  
Mitotic Chromosomes ◽  
Nuclear Envelope Breakdown ◽  
Binding Domains ◽  
Chromosome Alignment ◽  
Rna Complexes

During mitosis, the genome is transformed from a decondensed, transcriptionally active state to a highly condensed, transcriptionally inactive state. Mitotic chromosome reorganization is marked by the general attenuation of transcription on chromosome arms, yet how the cell regulates nuclear and chromatin-associated RNAs after chromosome condensation and nuclear envelope breakdown is unknown. SAF-A/hnRNPU is an abundant nuclear protein with RNA-to-DNA tethering activity, coordinated by two spatially distinct nucleic acid–binding domains. Here we show that RNA is evicted from prophase chromosomes through Aurora-B–dependent phosphorylation of the SAF-A DNA-binding domain; failure to execute this pathway leads to accumulation of SAF-A–RNA complexes on mitotic chromosomes, defects in metaphase chromosome alignment, and elevated rates of chromosome missegregation in anaphase. This work reveals a role for Aurora-B in removing chromatin-associated RNAs during prophase and demonstrates that Aurora-B–dependent relocalization of SAF-A during cell division contributes to the fidelity of chromosome segregation.

scholarly journals Phosphoinositide 3-kinase β regulates chromosome segregation in mitosis

2012 ◽  
Vol 23 (23) ◽  
pp. 4526-4542 ◽  
Author(s):  
Virginia Silió ◽  
Javier Redondo-Muñoz ◽  
Ana C. Carrera
Keyword(s):  
Chromosome Segregation ◽  
Genomic Stability ◽  
Pi3k Pathway ◽  
S Phase ◽  
Spindle Orientation ◽  
Aurora B ◽  
Pi3k Activity ◽  
Optimal Function ◽  
Phosphoinositide 3 Kinase ◽  
Phase Entry

Class IA phosphoinositide 3-kinases (PI3K) are enzymes composed of a p85 regulatory and a p110 catalytic subunit that control formation of 3-poly-phosphoinositides (PIP3). The PI3K pathway regulates cell survival, migration, and division, and is mutated in approximately half of human tumors. For this reason, it is important to define the function of the ubiquitous PI3K subunits, p110α and p110β. Whereas p110α is activated at G1-phase entry and promotes protein synthesis and gene expression, p110β activity peaks in S phase and regulates DNA synthesis. PI3K activity also increases at the onset of mitosis, but the isoform activated is unknown; we have examined p110α and p110β function in mitosis. p110α was activated at mitosis entry and regulated early mitotic events, such as PIP3 generation, prometaphase progression, and spindle orientation. In contrast, p110β was activated near metaphase and controlled dynein/dynactin and Aurora B activities in kinetochores, chromosome segregation, and optimal function of the spindle checkpoint. These results reveal a p110β function in preserving genomic stability during mitosis.

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