scholarly journals TAO1 kinase maintains chromosomal stability by facilitating proper congression of chromosomes

Open Biology ◽  
2014 ◽  
Vol 4 (6) ◽  
pp. 130108 ◽  
Author(s):  
Roshan L. Shrestha ◽  
Naoka Tamura ◽  
Anna Fries ◽  
Nicolas Levin ◽  
Joanna Clark ◽  
...  
Keyword(s):  
Error Correction ◽  
Chromosomal Instability ◽  
Spindle Checkpoint ◽  
Human Cells ◽  
Microtubule Dynamics ◽  
Regulatory Pathways ◽  
Chromosomal Stability ◽  
Microtubule Attachment ◽  
Drug Treatments

Chromosomal instability can arise from defects in chromosome–microtubule attachment. Using a variety of drug treatments, we show that TAO1 kinase is required for ensuring the normal congression of chromosomes. Depletion of TAO1 reduces the density of growing interphase and mitotic microtubules in human cells, showing TAO1's role in controlling microtubule dynamics. We demonstrate the aneugenic nature of chromosome–microtubule attachment defects in TAO1-depleted cells using an error-correction assay. Our model further strengthens the emerging paradigm that microtubule regulatory pathways are important for resolving erroneous kinetochore–microtubule attachments and maintaining the integrity of the genome, regardless of the spindle checkpoint status.

scholarly journals The wages of CIN

2008 ◽  
Vol 180 (4) ◽  
pp. 661-663 ◽  
Author(s):  
Karen W. Yuen ◽  
Arshad Desai
Keyword(s):  
Cancer Cells ◽  
Solid Tumors ◽  
Chromosomal Instability ◽  
Chromosome Instability ◽  
Spindle Checkpoint ◽  
Human Cells ◽  
Normal Cells ◽  
Chromosome Missegregation ◽  
Cell Biol ◽  
The Relationship

Aneuploidy and chromosome instability (CIN) are hallmarks of the majority of solid tumors, but the relationship between them is not well understood. In this issue, Thompson and Compton (Thompson, S.L., and D.A. Compton. 2008. Examining the link between chromosomal instability and aneuploidy in human cells. J. Cell. Biol. 180:665–672) investigate the mechanism of CIN in cancer cells and find that CIN arises primarily from defective kinetochore–spindle attachments that evade detection by the spindle checkpoint and persist into anaphase. They also explore the consequences of artificially elevating chromosome missegregation in otherwise karyotypically normal cells. Their finding that induced aneuploidy is rapidly selected against suggests that the persistence of aneuploid cells in tumors requires not only chromosome missegregation but also additional, as yet poorly defined events.

scholarly journals MKLP2 functions in early mitosis to ensure proper chromosome congression

2021 ◽  
Author(s):  
Morgan S Schrock ◽  
Luke Scarberry ◽  
Benjamin R Stromberg ◽  
Claire Sears ◽  
Adrian E Torres ◽  
...  
Keyword(s):  
Error Correction ◽  
Small Molecule ◽  
Hela Cells ◽  
Chromosomal Instability ◽  
Direct Evidence ◽  
Aurora Kinase ◽  
Downstream Target ◽  
Microtubule Attachment ◽  
Chromosome Congression ◽  
Early Mitosis

Mitotic kinesin-like protein 2 (MKLP2) is a motor protein with a well-established function in promoting cytokinesis. However, our results with siRNAs targeting MKLP2 and small molecule inhibitors of MKLP2 (MKLP2i) along with the observations of others suggested a function earlier in mitosis, prior to anaphase. In this study we provide direct evidence that MKLP2 facilitates chromosome congression in prometaphase. We employed live imaging to observe HeLa cells with fluorescently tagged histones treated with MKLP2i and discovered a pronounced chromosome congression defect. We show that MKLP2 inhibited cells had a significant increase in unstable kinetochore-microtubule attachments due to impaired error correction of syntelic attachments. We propose that MKLP2 mediates kinetochore microtubule attachment stability by regulating Aurora Kinase and a downstream target, pHEC1 (Ser 55). Lastly, we show that MKLP2 inhibition results in aneuploidy, confirming that MKLP2 safeguards cells against chromosomal instability.

scholarly journals α-Tubulin detyrosination impairs mitotic error correction by suppressing MCAK centromeric activity

2020 ◽  
Vol 219 (4) ◽  
Author(s):  
Luísa T. Ferreira ◽  
Bernardo Orr ◽  
Girish Rajendraprasad ◽  
António J. Pereira ◽  
Carolina Lemos ◽  
...  
Keyword(s):  
Error Correction ◽  
Posttranslational Modification ◽  
Chromosomal Instability ◽  
Experimental Manipulation ◽  
Microtubule Dynamics ◽  
Global Impact ◽  
Human Cancers ◽  
Microtubule Stability ◽  
Tubulin Tyrosine Ligase

Incorrect kinetochore–microtubule attachments during mitosis can lead to chromosomal instability, a hallmark of human cancers. Mitotic error correction relies on the kinesin-13 MCAK, a microtubule depolymerase whose activity in vitro is suppressed by α-tubulin detyrosination—a posttranslational modification enriched on long-lived microtubules. However, whether and how MCAK activity required for mitotic error correction is regulated by α-tubulin detyrosination remains unknown. Here we found that detyrosinated α-tubulin accumulates on correct, more stable, kinetochore–microtubule attachments. Experimental manipulation of tubulin tyrosine ligase (TTL) or carboxypeptidase (Vasohibins-SVBP) activities to constitutively increase α-tubulin detyrosination near kinetochores compromised efficient error correction, without affecting overall kinetochore microtubule stability. Rescue experiments indicate that MCAK centromeric activity was required and sufficient to correct the mitotic errors caused by excessive α-tubulin detyrosination independently of its global impact on microtubule dynamics. Thus, microtubules are not just passive elements during mitotic error correction, and the extent of α-tubulin detyrosination allows centromeric MCAK to discriminate correct vs. incorrect kinetochore–microtubule attachments, thereby promoting mitotic fidelity.

scholarly journals Delineating the contribution of Spc105-bound PP1 to spindle checkpoint silencing and kinetochore microtubule attachment regulation

2019 ◽  
Vol 218 (12) ◽  
pp. 3926-3942 ◽  
Author(s):  
Babhrubahan Roy ◽  
Vikash Verma ◽  
Janice Sim ◽  
Adrienne Fontan ◽  
Ajit P. Joglekar
Keyword(s):  
Cell Division ◽  
Error Correction ◽  
Chromosome Segregation ◽  
Protein Phosphatase ◽  
Spindle Assembly Checkpoint ◽  
Spindle Checkpoint ◽  
Spindle Assembly ◽  
Protein Phosphatase 1 ◽  
Microtubule Attachment ◽  
Error Correction Mechanism

Accurate chromosome segregation during cell division requires the spindle assembly checkpoint (SAC), which detects unattached kinetochores, and an error correction mechanism that destabilizes incorrect kinetochore–microtubule attachments. While the SAC and error correction are both regulated by protein phosphatase 1 (PP1), which silences the SAC and stabilizes kinetochore–microtubule attachments, how these distinct PP1 functions are coordinated remains unclear. Here, we investigate the contribution of PP1, docked on its conserved kinetochore receptor Spc105/Knl1, to SAC silencing and attachment regulation. We find that Spc105-bound PP1 is critical for SAC silencing but dispensable for error correction; in fact, reduced PP1 docking on Spc105 improved chromosome segregation and viability of mutant/stressed states. We additionally show that artificially recruiting PP1 to Spc105/Knl1 before, but not after, chromosome biorientation interfered with error correction. These observations lead us to propose that recruitment of PP1 to Spc105/Knl1 is carefully regulated to ensure that chromosome biorientation precedes SAC silencing, thereby ensuring accurate chromosome segregation.

scholarly journals Polo-like kinase-1 regulates kinetochore–microtubule dynamics and spindle checkpoint silencing

2012 ◽  
Vol 198 (4) ◽  
pp. 491-499 ◽  
Author(s):  
Dan Liu ◽  
Olga Davydenko ◽  
Michael A. Lampson
Keyword(s):  
High Activity ◽  
Spindle Checkpoint ◽  
Mitotic Arrest ◽  
Microtubule Dynamics ◽  
Signaling Proteins ◽  
Dynamic Localization ◽  
Checkpoint Signaling ◽  
Microtubule Attachment

Polo-like kinase-1 (Plk1) is a highly conserved kinase with multiple mitotic functions. Plk1 localizes to prometaphase kinetochores and is reduced at metaphase kinetochores, similar to many checkpoint signaling proteins, but Plk1 is not required for spindle checkpoint function. Plk1 is also implicated in stabilizing kinetochore–microtubule attachments, but these attachments are most stable when kinetochore Plk1 levels are low at metaphase. Therefore, it is unclear how Plk1 function at kinetochores can be understood in the context of its dynamic localization. In this paper, we show that Plk1 activity suppresses kinetochore–microtubule dynamics to stabilize initial attachments in prometaphase, and Plk1 removal from kinetochores is necessary to maintain dynamic microtubules in metaphase. Constitutively targeting Plk1 to kinetochores maintained high activity at metaphase, leading to reduced interkinetochore tension and intrakinetochore stretch, a checkpoint-dependent mitotic arrest, and accumulation of microtubule attachment errors. Together, our data show that Plk1 dynamics at kinetochores control two critical mitotic processes: initially establishing correct kinetochore–microtubule attachments and subsequently silencing the spindle checkpoint.

scholarly journals Knockdown of αII spectrin in normal human cells by siRNA leads to chromosomal instability and decreased DNA interstrand cross-link repair

2009 ◽  
Vol 381 (2) ◽  
pp. 288-293 ◽  
Author(s):  
Laura W. McMahon ◽  
Pan Zhang ◽  
Deepa M. Sridharan ◽  
Joel A. Lefferts ◽  
Muriel W. Lambert
Keyword(s):  
Chromosomal Instability ◽  
Human Cells ◽  
Cross Link ◽  
Normal Human ◽  
Normal Human Cells

scholarly journals Chromosome segregation fidelity is controlled by small changes in phospho-occupancy at the kinetochore-microtubule interface

2021 ◽  
Author(s):  
Thomas J. Kucharski ◽  
Rufus Hards ◽  
Kristina M. Godek ◽  
Scott A. Gerber ◽  
Duane A. Compton
Keyword(s):  
Error Correction ◽  
Chromosome Segregation ◽  
Dynamic Range ◽  
High Sensitivity ◽  
Cyclin B1 ◽  
Quantitative Mass Spectrometry ◽  
Kinetochore Protein ◽  
Microtubule Attachment ◽  
Different Types ◽  
Narrow Dynamic Range

SummaryKinetochore protein phosphorylation promotes the correction of erroneous microtubule attachments to ensure faithful chromosome segregation during cell division. Determining how phosphorylation executes error correction requires an understanding of whether kinetochore substrates are completely (i.e. all-or-none) or only fractionally phosphorylated. Using quantitative mass spectrometry (MS), we measured phospho-occupancy on the conserved kinetochore protein Hec1 (NDC80) that directly binds microtubules. None of the positions measured exceeded ∼50% phospho-occupancy, and the cumulative phospho-occupancy changed by only ∼20% in response to changes in microtubule attachment status. The narrow dynamic range of phospho-occupancy is maintained by ongoing phosphatase activity. Further, both Cdk1-Cyclin B1 and Aurora kinases phosphorylate Hec1 to enhance error correction in response to different types of microtubule attachment errors. Thus, networks of kinases and phosphatases maintain low inherent phospho-occupancy to promote microtubule attachment to kinetochores while providing for high sensitivity of kinetochore-microtubule attachments to very small changes in phospho-occupancy to ensure high mitotic fidelity.

scholarly journals Cells protect chromosome-microtubule attachments, independent of biorientation, using an Astrin-PP1 and CyclinB-CDK1 feedback loop

2020 ◽  
Author(s):  
Duccio Conti ◽  
Xinhong Song ◽  
Roshan L. Shrestha ◽  
Dominique Braun ◽  
Viji M Draviam
Keyword(s):  
Chromosomal Instability ◽  
Feedback Loop ◽  
Cyclin B ◽  
Macromolecular Structure ◽  
Aurora B ◽  
Unique Role ◽  
Spindle Poles ◽  
Microtubule Attachment ◽  
Segregation Of Chromosomes

Defects in chromosome-microtubule attachment can cause chromosomal instability, associated with infertility and aggressive cancers. Chromosome-microtubule attachment is mediated by a large macromolecular structure, the kinetochore. Kinetochore pairs are bioriented and pulled by microtubules from opposing spindle poles to ensure the equal segregation of chromosomes. Kinetochore-microtubule attachments lacking opposing-pull are detached by Aurora-B/Ipl1; yet, how mono-oriented attachments that are a prerequisite for biorientation, but lacking opposing-pull are spared is unclear. Using an RNAi-mediated screen, we uncover a unique role for the Astrin-SKAP complex in protecting mono-oriented attachments. We provide the first evidence for how a microtubule-end associated protein senses outer-kinetochore changes specific to end-on attachments and assembles into an outer kinetochore crescent to stabilise mature attachments. We find that Astrin-PP1 and Cyclin-B-CDK1 activities counteract each other to preserve mono-oriented attachments. Thus, cells are not only surveying chromosome-microtubule attachment errors, but they are also actively sensing and stabilising mature attachments independent of biorientation.

scholarly journals Securin Is Not Required for Chromosomal Stability in Human Cells

PLoS Biology ◽  
2005 ◽  
Vol 3 (12) ◽  
pp. e416 ◽  
Author(s):  
Katrin Pfleghaar ◽  
Simone Heubes ◽  
Jürgen Cox ◽  
Olaf Stemmann ◽  
Michael R Speicher
Keyword(s):  
Human Cells ◽  
Chromosomal Stability
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