scholarly journals Aurora A kinase phosphorylates Hec1 to regulate metaphase kinetochore–microtubule dynamics

2017 ◽  
Vol 217 (1) ◽  
pp. 163-177 ◽  
Author(s):  
Keith F. DeLuca ◽  
Amanda Meppelink ◽  
Amanda J. Broad ◽  
Jeanne E. Mick ◽  
Olve B. Peersen ◽  
...  
Keyword(s):  
Chromosome Segregation ◽  
Microtubule Dynamics ◽  
Aurora B ◽  
Aurora A Kinase ◽  
Aurora A ◽  
Tail Domain ◽  
Mitotic Chromosomes ◽  
Metaphase Chromosomes ◽  
Mitotic Kinases ◽  
Microtubule Attachment

Precise regulation of kinetochore–microtubule attachments is essential for successful chromosome segregation. Central to this regulation is Aurora B kinase, which phosphorylates kinetochore substrates to promote microtubule turnover. A critical target of Aurora B is the N-terminal “tail” domain of Hec1, which is a component of the NDC80 complex, a force-transducing link between kinetochores and microtubules. Although Aurora B is regarded as the “master regulator” of kinetochore–microtubule attachment, other mitotic kinases likely contribute to Hec1 phosphorylation. In this study, we demonstrate that Aurora A kinase regulates kinetochore–microtubule dynamics of metaphase chromosomes, and we identify Hec1 S69, a previously uncharacterized phosphorylation target site in the Hec1 tail, as a critical Aurora A substrate for this regulation. Additionally, we demonstrate that Aurora A kinase associates with inner centromere protein (INCENP) during mitosis and that INCENP is competent to drive accumulation of the kinase to the centromere region of mitotic chromosomes. These findings reveal that both Aurora A and B contribute to kinetochore–microtubule attachment dynamics, and they uncover an unexpected role for Aurora A in late mitosis.

scholarly journals Aurora A and Aurora B jointly coordinate chromosome segregation and anaphase microtubule dynamics

2011 ◽  
Vol 195 (7) ◽  
pp. 1103-1113 ◽  
Author(s):  
Nadia Hégarat ◽  
Ewan Smith ◽  
Gowri Nayak ◽  
Shunichi Takeda ◽  
Patrick A. Eyers ◽  
...  
Keyword(s):  
Chromosome Segregation ◽  
Aurora B ◽  
Aurora A Kinase ◽  
Aurora A ◽  
Daughter Cells ◽  
Conditional Deletion ◽  
Alignment Problem ◽  
Single Nucleus ◽  
Bipolar Spindles ◽  
Dt40 Cells

We established a conditional deletion of Aurora A kinase (AurA) in Cdk1 analogue-sensitive DT40 cells to analyze AurA knockout phenotypes after Cdk1 activation. In the absence of AurA, cells form bipolar spindles but fail to properly align their chromosomes and exit mitosis with segregation errors. The resulting daughter cells exhibit a variety of phenotypes and are highly aneuploid. Aurora B kinase (AurB)–inhibited cells show a similar chromosome alignment problem and cytokinesis defects, resulting in binucleate daughter cells. Conversely, cells lacking AurA and AurB activity exit mitosis without anaphase, forming polyploid daughter cells with a single nucleus. Strikingly, inhibition of both AurA and AurB results in a failure to depolymerize spindle microtubules (MTs) in anaphase after Cdk1 inactivation. These results suggest an essential combined function of AurA and AurB in chromosome segregation and anaphase MT dynamics.

scholarly journals Identification of a novel nucleolar protein complex required for mitotic chromosome segregation through centromeric accumulation of Aurora B

2020 ◽  
Vol 48 (12) ◽  
pp. 6583-6596
Author(s):  
Akiko Fujimura ◽  
Yuki Hayashi ◽  
Kazashi Kato ◽  
Yuichiro Kogure ◽  
Mutsuro Kameyama ◽  
...  
Keyword(s):  
Chromosome Segregation ◽  
Protein Complex ◽  
Metaphase Plate ◽  
Nucleolar Protein ◽  
Aurora B ◽  
Mitotic Progression ◽  
Mitotic Chromosomes ◽  
Nucleolar Proteins ◽  
Chromatid Cohesion ◽  
Wd Repeat

Abstract The nucleolus is a membrane-less nuclear structure that disassembles when cells undergo mitosis. During mitosis, nucleolar factors are thus released from the nucleolus and dynamically change their subcellular localization; however, their functions remain largely uncharacterised. Here, we found that a nucleolar factor called nucleolar protein 11 (NOL11) forms a protein complex with two tryptophan-aspartic acid (WD) repeat proteins named WD-repeat protein 43 (WDR43) and Cirhin in mitotic cells. This complex, referred to here as the NWC (NOL11-WDR43-Cirhin) complex, exists in nucleoli during interphase and translocates to the periphery of mitotic chromosomes, i.e., perichromosomal regions. During mitotic progression, both the congression of chromosomes to the metaphase plate and sister chromatid cohesion are impaired in the absence of the NWC complex, as it is required for the centromeric enrichment of Aurora B and the associating phosphorylation of histone H3 at threonine 3. These results reveal the characteristics of a novel protein complex consisting of nucleolar proteins, which is required for regulating kinetochores and centromeres to ensure faithful chromosome segregation.

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 Inhibition of Aurora B Kinase Blocks Chromosome Segregation, Overrides the Spindle Checkpoint, and Perturbs Microtubule Dynamics in Mitosis

2002 ◽  
Vol 12 (11) ◽  
pp. 900-905 ◽  
Author(s):  
Marko J. Kallio ◽  
Mark L. McCleland ◽  
P.Todd Stukenberg ◽  
Gary J. Gorbsky
Keyword(s):  
Chromosome Segregation ◽  
Spindle Checkpoint ◽  
Microtubule Dynamics ◽  
Aurora B ◽  
Aurora B Kinase

scholarly journals Aurora-C Kinase Deficiency Causes Cytokinesis Failure in Meiosis I and Production of Large Polyploid Oocytes in Mice

2010 ◽  
Vol 21 (14) ◽  
pp. 2371-2383 ◽  
Author(s):  
Kuo-Tai Yang ◽  
Shu-Kuei Li ◽  
Chih-Chieh Chang ◽  
Chieh-Ju C. Tang ◽  
Yi-Nan Lin ◽  
...  
Keyword(s):  
Chromosome Segregation ◽  
Female Mouse ◽  
Histone H3 ◽  
Aurora B ◽  
Binding Motif ◽  
Mouse Oocytes ◽  
Microtubule Attachment ◽  
H3 Phosphorylation ◽  
Histone H3 Phosphorylation ◽  
Meiosis I

We previously isolated Aurora-C/Aie1 in a screen for kinases expressed in mouse sperm and eggs. Here, we show the localization of endogenous Aurora-C and examine its roles during female mouse meiosis. Aurora-C was detected at the centromeres and along the chromosome arms in prometaphase I–metaphase I and was concentrated at centromeres at metaphase II, in which Aurora-C also was phosphorylated at Thr171. During the anaphase I–telophase I transition, Aurora-C was dephosphorylated and relocalized to the midzone and midbody. Microinjection of the kinase-deficient Aurora-C (AurC-KD) mRNA into mouse oocytes significantly inhibited Aurora-C activity and caused multiple defects, including chromosome misalignment, abnormal kinetochore–microtubule attachment, premature chromosome segregation, and cytokinesis failure in meiosis I. Furthermore, AurC-KD reduced Aurora-C and histone H3 phosphorylation and inhibited kinetochore localization of Bub1 and BubR1. Similar effects also were observed in the oocytes injected with INCNEP-delIN mRNAs, in which the Aurora-C binding motif was removed. The most dramatic effect observed in AurC-KD–injected oocytes is cytokinesis failure in meiosis I, resulting in producing large polyploid oocytes, a pattern similar to Aurora-C deficiency human spermatozoa. Surprisingly, we detected no Aurora-B protein in mouse oocytes. We propose that Aurora-C, but not Aurora-B, plays essential roles in female mouse meiosis.

scholarly journals AIR-2: An Aurora/Ipl1-related Protein Kinase Associated with Chromosomes and Midbody Microtubules Is Required for Polar Body Extrusion and Cytokinesis in Caenorhabditis elegans Embryos

1998 ◽  
Vol 143 (6) ◽  
pp. 1635-1646 ◽  
Author(s):  
Jill M. Schumacher ◽  
Andy Golden ◽  
Peter J. Donovan
Keyword(s):  
Caenorhabditis Elegans ◽  
Chromosome Segregation ◽  
Polar Body ◽  
Mitotic Division ◽  
Mitotic Chromosomes ◽  
Metaphase Chromosomes ◽  
Cell Cycles ◽  
Polar Bodies ◽  
Multiple Cell ◽  
Polar Body Extrusion

An emerging family of kinases related to the Drosophila Aurora and budding yeast Ipl1 proteins has been implicated in chromosome segregation and mitotic spindle formation in a number of organisms. Unlike other Aurora/Ipl1-related kinases, the Caenorhabditis elegans orthologue, AIR-2, is associated with meiotic and mitotic chromosomes. AIR-2 is initially localized to the chromosomes of the most mature prophase I–arrested oocyte residing next to the spermatheca. This localization is dependent on the presence of sperm in the spermatheca. After fertilization, AIR-2 remains associated with chromosomes during each meiotic division. However, during both meiotic anaphases, AIR-2 is present between the separating chromosomes. AIR-2 also remains associated with both extruded polar bodies. In the embryo, AIR-2 is found on metaphase chromosomes, moves to midbody microtubules at anaphase, and then persists at the cytokinesis remnant. Disruption of AIR-2 expression by RNA- mediated interference produces entire broods of one-cell embryos that have executed multiple cell cycles in the complete absence of cytokinesis. The embryos accumulate large amounts of DNA and microtubule asters. Polar bodies are not extruded, but remain in the embryo where they continue to replicate. The cytokinesis defect appears to be late in the cell cycle because transient cleavage furrows initiate at the proper location, but regress before the division is complete. Additionally, staining with a marker of midbody microtubules revealed that at least some of the components of the midbody are not well localized in the absence of AIR-2 activity. Our results suggest that during each meiotic and mitotic division, AIR-2 may coordinate the congression of metaphase chromosomes with the subsequent events of polar body extrusion and cytokinesis.

scholarly journals Aurora at the pole and equator: overlapping functions of Aurora kinases in the mitotic spindle

Open Biology ◽  
2013 ◽  
Vol 3 (3) ◽  
pp. 120185 ◽  
Author(s):  
Helfrid Hochegger ◽  
Nadia Hégarat ◽  
Jose B. Pereira-Leal
Keyword(s):  
Chromosome Segregation ◽  
Mitotic Spindle ◽  
Aurora Kinase ◽  
Spindle Pole ◽  
Aurora A ◽  
Mitotic Progression ◽  
Aurora Kinases ◽  
Mitotic Kinases ◽  
Chromosome Alignment ◽  
Spindle Microtubules

The correct assembly and timely disassembly of the mitotic spindle is crucial for the propagation of the genome during cell division. Aurora kinases play a central role in orchestrating bipolar spindle establishment, chromosome alignment and segregation. In most eukaryotes, ranging from amoebas to humans, Aurora activity appears to be required both at the spindle pole and the kinetochore, and these activities are often split between two different Aurora paralogues, termed Aurora A and B. Polar and equatorial functions of Aurora kinases have generally been considered separately, with Aurora A being mostly involved in centrosome dynamics, whereas Aurora B coordinates kinetochore attachment and cytokinesis. However, double inactivation of both Aurora A and B results in a dramatic synergy that abolishes chromosome segregation. This suggests that these two activities jointly coordinate mitotic progression. Accordingly, recent evidence suggests that Aurora A and B work together in both spindle assembly in metaphase and disassembly in anaphase. Here, we provide an outlook on these shared functions of the Auroras, discuss the evolution of this family of mitotic kinases and speculate why Aurora kinase activity may be required at both ends of the spindle microtubules.

scholarly journals Aurora B switches relative strength between kinetochore–microtubule attachment modes to promote error correction

2018 ◽  
Author(s):  
Harinath Doodhi ◽  
Taciana Kasciukovic ◽  
Lesley Clayton ◽  
Tomoyuki U. Tanaka
Keyword(s):  
Error Correction ◽  
Chromosome Segregation ◽  
Relative Strength ◽  
Lateral Side ◽  
Aurora B ◽  
Spindle Poles ◽  
Microtubule Attachment ◽  
Attachment Strength ◽  
Dam1 Complex

AbstractFor proper chromosome segregation, sister kinetochores must interact with microtubules from opposite spindle poles; this is called bi-orientation. To establish bi-orientation prior to chromosome segregation, any aberrant kinetochore–microtubule interaction must be resolved (error correction) by Aurora B kinase that phosphorylates outer kinetochore components. Aurora B differentially regulates kinetochore attachment to the microtubule plus end and its lateral side (end-on and lateral attachment, respectively). However, it is still not fully understood how kinetochore–microtubule interactions are exchanged during error correction. Here we reconstituted the kinetochore–microtubule interface of budding yeast in vitro by attaching the Ndc80 complexes (Ndc80C) to nanobeads. These Ndc80C–nanobeads recapitulated in vitro the lateral and end-on attachments of authentic kinetochores, on dynamic microtubules loaded with the Dam1 complex. This in vitro assay enabled the direct comparison of lateral and end-on attachment strength and showed that Dam1 phosphorylation by Aurora B makes the end-on attachment weaker than the lateral attachment. We suggest that the Dam1 phosphorylation weakens interaction with the Ndc80 complex, disrupts the end-on attachment and promotes the exchange to a new lateral attachment, leading to error correction. Our study reveals a fundamental mechanism of error correction for establishment of bi-orientation.

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 Mio depletion links mTOR regulation to Aurora A and Plk1 activation at mitotic centrosomes

2015 ◽  
Vol 210 (1) ◽  
pp. 45-62 ◽  
Author(s):  
Melpomeni Platani ◽  
Laura Trinkle-Mulcahy ◽  
Michael Porter ◽  
A. Arockia Jeyaprakash ◽  
William C. Earnshaw
Keyword(s):  
Mitotic Spindle ◽  
Critical Role ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Signaling ◽  
Aurora A Kinase ◽  
Aurora A ◽  
Spindle Formation ◽  
Major Function ◽  
Mitotic Kinases ◽  
Spindle Poles

Coordination of cell growth and proliferation in response to nutrient supply is mediated by mammalian target of rapamycin (mTOR) signaling. In this study, we report that Mio, a highly conserved member of the SEACAT/GATOR2 complex necessary for the activation of mTORC1 kinase, plays a critical role in mitotic spindle formation and subsequent chromosome segregation by regulating the proper concentration of active key mitotic kinases Plk1 and Aurora A at centrosomes and spindle poles. Mio-depleted cells showed reduced activation of Plk1 and Aurora A kinase at spindle poles and an impaired localization of MCAK and HURP, two key regulators of mitotic spindle formation and known substrates of Aurora A kinase, resulting in spindle assembly and cytokinesis defects. Our results indicate that a major function of Mio in mitosis is to regulate the activation/deactivation of Plk1 and Aurora A, possibly by linking them to mTOR signaling in a pathway to promote faithful mitotic progression.

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