scholarly journals Silencing the spindle assembly checkpoint: Let’s play Polo!

2020 ◽  
Vol 219 (12) ◽  
Author(s):  
Giorgia Benzi ◽  
Simonetta Piatti
Keyword(s):  
Spindle Assembly Checkpoint ◽  
Protein Phosphatases ◽  
Spindle Assembly ◽  
Critical Function ◽  
Checkpoint Signaling ◽  
Polo Kinase

Silencing of the spindle assembly checkpoint involves two protein phosphatases, PP1 and PP2A-B56, that are thought to extinguish checkpoint signaling through dephosphorylation of a checkpoint scaffold at kinetochores. In this issue, Cordeiro et al. (2020. J. Cell Biol.https://doi.org/10.1083/jcb.202002020) now show that a critical function of these phosphatases in checkpoint silencing is removal of Polo kinase at kinetochores, which would otherwise autonomously sustain the checkpoint.

scholarly journals Author response: Bub3 reads phosphorylated MELT repeats to promote spindle assembly checkpoint signaling

2013 ◽  
Author(s):  
Ivana Primorac ◽  
John R Weir ◽  
Elena Chiroli ◽  
Fridolin Gross ◽  
Ingrid Hoffmann ◽  
...  
Keyword(s):  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Author Response ◽  
Checkpoint Signaling

scholarly journals A stochastic model for error correction of kinetochore-microtubule attachments and its coupling to the spindle assembly checkpoint

2019 ◽  
Author(s):  
Anand Banerjee ◽  
Neil Adames ◽  
Jean Peccoud ◽  
John J. Tyson
Keyword(s):  
Stochastic Model ◽  
Error Correction ◽  
Spindle Assembly Checkpoint ◽  
Budding Yeast ◽  
Analytical Formula ◽  
Spindle Assembly ◽  
Experimental Information ◽  
Checkpoint Signaling ◽  
Balance Point ◽  
Checkpoint Signal

AbstractTo divide replicated chromosomes equally between daughter cells kinetochores must attach to microtubules emanating from opposite poles of the mitotic spindle. Two mechanisms, namely, error correction and ‘spindle assembly checkpoint’ work together to facilitate this process. The error correction mechanism recognizes and detaches erroneous kinetochore-microtubule attachments, and the spindle assembly checkpoint delays the onset of anaphase until all the kinetochores are properly attached. Kinases and phosphatases at the kinetochore play a key role in proper functioning of these two mechanisms. Here we present a stochastic model to study how the opposing activities of kinases and phosphatases at the kinetochore affect error correction of kinetochore-microtubule attachments and checkpoint signaling in budding yeast, Saccharomyces cerevisiae. We show that error correction and biorientation of chromosomes occurs efficiently when the ratio between kinase activity of Ipl1 and the activity of an opposing phosphatase is a constant (balance point), and derive an approximate analytical formula that defines the balance point. Analysis of the coupling of the spindle assembly checkpoint signal to error correction shows that its strength remains high when the Ipl1 activity is equal to (or larger than) the value specified by the balance point, and the activity of another kinase, Mps1, is much larger (approximately 30 times larger) than its opposing phosphatase (PP1). We also find that the geometrical orientation of sister chromatids does not significantly improve the probability of their reaching biorientation, which depends entirely on Ipl1-dependent microtubule detachment.Author summaryThe kinetochore, the master regulator of chromosome segregation, integrates signals from different chromosome attachment states to generate an appropriate response, like the destabilization of erroneous kinetochore-microtubule attachments, stabilization of correct attachments, maintenance of the spindle assembly checkpoint signal until all kinetochores are properly attached, and finally silencing of checkpoint when biorientation is achieved. At a molecular level the job is carried out by kinases and phosphatases. The complexity of the interactions between these kinases and phosphatases makes intuitive analysis of the control network impossible, and a systems-level model is needed to put experimental information together and to generate testable hypotheses. Here we present such a model for the process of error correction and its coupling to the spindle assembly checkpoint in budding yeast. Using the model, we characterize the balance between kinase and phosphatase activities required for removing erroneous attachments and then establishing correct stable attachments between kinetochore and microtubule. We also analyze how the balance affects the strength of the spindle assembly checkpoint signal.

scholarly journals Bub3 reads phosphorylated MELT repeats to promote spindle assembly checkpoint signaling

eLife ◽  
2013 ◽  
Vol 2 ◽  
Author(s):  
Ivana Primorac ◽  
John R Weir ◽  
Elena Chiroli ◽  
Fridolin Gross ◽  
Ingrid Hoffmann ◽  
...  
Keyword(s):  
Chromosome Segregation ◽  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Binding Mode ◽  
Signaling Networks ◽  
Checkpoint Signaling ◽  
Checkpoint Proteins ◽  
Downstream Signaling ◽  
Signaling Components ◽  
Insight Into

Regulation of macromolecular interactions by phosphorylation is crucial in signaling networks. In the spindle assembly checkpoint (SAC), which enables errorless chromosome segregation, phosphorylation promotes recruitment of SAC proteins to tensionless kinetochores. The SAC kinase Mps1 phosphorylates multiple Met-Glu-Leu-Thr (MELT) motifs on the kinetochore subunit Spc105/Knl1. The phosphorylated MELT motifs (MELTP) then promote recruitment of downstream signaling components. How MELTP motifs are recognized is unclear. In this study, we report that Bub3, a 7-bladed β-propeller, is the MELTP reader. It contains an exceptionally well-conserved interface that docks the MELTP sequence on the side of the β-propeller in a previously unknown binding mode. Mutations targeting the Bub3 interface prevent kinetochore recruitment of the SAC kinase Bub1. Crucially, they also cause a checkpoint defect, showing that recognition of phosphorylated targets by Bub3 is required for checkpoint signaling. Our data provide the first detailed mechanistic insight into how phosphorylation promotes recruitment of checkpoint proteins to kinetochores.

scholarly journals BubR1 Promotes Bub3-Dependent APC/C Inhibition during Spindle Assembly Checkpoint Signaling

2017 ◽  
Vol 27 (19) ◽  
pp. 2915-2927.e7 ◽  
Author(s):  
Katharina Overlack ◽  
Tanja Bange ◽  
Florian Weissmann ◽  
Alex C. Faesen ◽  
Stefano Maffini ◽  
...  
Keyword(s):  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Checkpoint Signaling

scholarly journals Ectopic Activation of the Spindle Assembly Checkpoint Signaling Cascade Reveals Its Biochemical Design

2019 ◽  
Vol 29 (1) ◽  
pp. 104-119.e10 ◽  
Author(s):  
Chu Chen ◽  
Ian P. Whitney ◽  
Anand Banerjee ◽  
Carlos Sacristan ◽  
Palak Sekhri ◽  
...  
Keyword(s):  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Signaling Cascade ◽  
Checkpoint Signaling ◽  
Ectopic Activation

scholarly journals Spindle assembly checkpoint signaling and sister chromatid cohesion are disrupted by HPV E6-mediated transformation

2017 ◽  
Vol 28 (15) ◽  
pp. 2035-2041 ◽  
Author(s):  
Hazheen K. Shirnekhi ◽  
Erin P. Kelley ◽  
Jennifer G. DeLuca ◽  
Jacob A. Herman
Keyword(s):  
Cancer Progression ◽  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Mitotic Exit ◽  
Human Papillomaviruses ◽  
Checkpoint Signaling ◽  
Hpv E6 ◽  
Chromatid Cohesion ◽  
E6 And E7 ◽  
Transforming Proteins

Aneuploidy, a condition that results from unequal partitioning of chromosomes during mitosis, is a hallmark of many cancers, including those caused by human papillomaviruses (HPVs). E6 and E7 are the primary transforming proteins in HPV that drive tumor progression. In this study, we stably expressed E6 and E7 in noncancerous RPE1 cells and analyzed the specific mitotic defects that contribute to aneuploidy in each cell line. We find that E6 expression results in multiple chromosomes associated with one or both spindle poles, causing a significant mitotic delay. In most cells, the misaligned chromosomes eventually migrated to the spindle equator, leading to mitotic exit. In some cells, however, mitotic exit occurred in the presence of pole-associated chromosomes. We determined that this premature mitotic exit is due to defects in spindle assembly checkpoint (SAC) signaling, such that cells are unable to maintain a prolonged mitotic arrest in the presence of unaligned chromosomes. This SAC defect is caused in part by a loss of kinetochore-associated Mad2 in E6-expressing cells. Our results demonstrate that E6-expressing cells exhibit previously unappreciated mitotic defects that likely contribute to HPV-mediated cancer progression.

Sign in / Sign up

Export Citation Format

Share Document