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Journal articles on the topic 'Mitotic slippage'

Author: Grafiati

Published: 4 June 2021

Last updated: 10 March 2023

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1

Lee, Kyunghee, Alison E. Kenny, and Conly L. Rieder. "Caspase activity is not required for the mitotic checkpoint or mitotic slippage in human cells." Molecular Biology of the Cell 22, no. 14 (July 15, 2011): 2470–79. http://dx.doi.org/10.1091/mbc.e11-03-0228.

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Biochemical studies suggest that caspase activity is required for a functional mitotic checkpoint (MC) and mitotic slippage. To test this directly, we followed nontransformed human telomerase immortalized human retinal pigment epithelia (RPE-1) cells through mitosis after inhibiting or depleting selected caspases. We found that inhibiting caspases individually, in combination, or in toto did not affect the duration or fidelity of mitosis in otherwise untreated cells. When satisfaction of the MC was prevented with 500 nM nocodazole or 2.5 μM dimethylenastron (an Eg5 inhibitor), 92–100% of RPE-1 cells slipped from mitosis in the presence of pan-caspase inhibitors or after simultaneously depleting caspase-3 and -9, and they did so with the same kinetics (∼21–22 h) as after treatment with nocodazole or Eg5 inhibitors alone. Surprisingly, inhibiting or depleting caspase-9 alone doubled the number of nocodazole-treated, but not Eg5-inhibited, cells that died in mitosis. In addition, inhibiting or depleting caspase-9 and -3 together accelerated the rate of slippage ∼40% (to ∼13–15 h). Finally, nocodazole-treated cells that recently slipped through mitosis in the presence or absence of pan-caspase inhibitors contained numerous BubR1 foci in their nuclei. From these data, we conclude that caspase activity is not required for a functional MC or for mitotic slippage.

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2

Brito, Daniela A., Zhenye Yang, and Conly L. Rieder. "Microtubules do not promote mitotic slippage when the spindle assembly checkpoint cannot be satisfied." Journal of Cell Biology 182, no. 4 (August 18, 2008): 623–29. http://dx.doi.org/10.1083/jcb.200805072.

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When the spindle assembly checkpoint (SAC) cannot be satisfied, cells exit mitosis via mitotic slippage. In microtubule (MT) poisons, slippage requires cyclin B proteolysis, and it appears to be accelerated in drug concentrations that allow some MT assembly. To determine if MTs accelerate slippage, we followed mitosis in human RPE-1 cells exposed to various spindle poisons. At 37°C, the duration of mitosis in nocodazole, colcemid, or vinblastine concentrations that inhibit MT assembly varied from 20 to 30 h, revealing that different MT poisons differentially depress the cyclin B destruction rate during slippage. The duration of mitosis in Eg5 inhibitors, which induce monopolar spindles without disrupting MT dynamics, was the same as in cells lacking MTs. Thus, in the presence of numerous unattached kinetochores, MTs do not accelerate slippage. Finally, compared with cells lacking MTs, exit from mitosis is accelerated over a range of spindle poison concentrations that allow MT assembly because the SAC becomes satisfied on abnormal spindles and not because slippage is accelerated.

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3

Cheng, Bing, and Karen Crasta. "Consequences of mitotic slippage for antimicrotubule drug therapy." Endocrine-Related Cancer 24, no. 9 (September 2017): T97—T106. http://dx.doi.org/10.1530/erc-17-0147.

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Antimicrotubule agents are commonly utilised as front-line therapies against several malignancies, either by themselves or as combination therapies. Cell-based studies have pinpointed the anti-proliferative basis of action to be a consequence of perturbation of microtubule dynamics leading to sustained activation of the spindle assembly checkpoint, prolonged mitotic arrest and mitotic cell death. However, depending on the biological context and cell type, cells may take an alternative route besides mitotic cell death via a process known as mitotic slippage. Here, mitotically arrested cells ‘slip’ to the next interphase without undergoing proper chromosome segregation and cytokinesis. These post-slippage cells in turn have two main cell fates, either cell death or a G1 arrest ensuing in senescence. In this review, we take a look at the factors determining mitotic cell death vs mitotic slippage, post-slippage cell fates and accompanying features, and their consequences for antimicrotubule drug treatment outcomes.

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4

Andreassen, P. R., and R. L. Margolis. "Microtubule dependency of p34cdc2 inactivation and mitotic exit in mammalian cells." Journal of Cell Biology 127, no. 3 (November 1, 1994): 789–802. http://dx.doi.org/10.1083/jcb.127.3.789.

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The protein kinase inhibitor 2-aminopurine induces checkpoint override and mitotic exit in BHK cells which have been arrested in mitosis by inhibitors of microtubule function (Andreassen, P. R., and R. L. Margolis. 1991. J. Cell Sci. 100:299-310). Mitotic exit is monitored by loss of MPM-2 antigen, by the reformation of nuclei, and by the extinction of p34cdc2-dependent H1 kinase activity. 2-AP-induced inactivation of p34cdc2 and mitotic exit depend on the assembly state of microtubules. During mitotic arrest generated by the microtubule assembly inhibitor nocodazole, the rate of mitotic exit induced by 2-AP decreases proportionally with increasing nocodazole concentrations. At nocodazole concentrations of 0.12 microgram/ml or greater, 2-AP induces no apparent exit through 75 min of treatment. In contrast, 2-AP brings about a rapid exit (t1/2 = 20 min) from mitotic arrest by taxol, a drug which causes inappropriate overassembly of microtubules. In control mitotic cells, p34cdc2 localizes to kinetochores, centrosomes, and spindle microtubules. We find that efficient exit from mitosis occurs under conditions where p34cdc2 remains associated with centrosomal microtubules, suggesting it must be present on these microtubules in order to be inactivated. Mitotic slippage, the natural reentry of cells into G1 during prolonged mitotic block, is also microtubule dependent. At high nocodazole concentrations slippage is prevented and mitotic arrest approaches 100%. We conclude that essential components of the machinery for exit from mitosis are present on the mitotic spindle, and that normal mitotic exit thereby may be regulated by the microtubule assembly state.

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5

Brandeis, Michael. "Slip slidin’ away of mitosis with CRL2Zyg11." Journal of Cell Biology 215, no. 2 (October 17, 2016): 143–45. http://dx.doi.org/10.1083/jcb.201609086.

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The spindle assembly checkpoint arrests mitotic cells by preventing degradation of cyclin B1 by the anaphase-promoting complex/cyclosome, but some cells evade this checkpoint and slip out of mitosis. Balachandran et al. (2016. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201601083) show that the E3 ligase CRL2ZYG11 degrades cyclin B1, allowing mitotic slippage.

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6

Balachandran, Riju S., Cassandra S. Heighington, Natalia G. Starostina, James W. Anderson, David L. Owen, Srividya Vasudevan, and Edward T. Kipreos. "The ubiquitin ligase CRL2ZYG11 targets cyclin B1 for degradation in a conserved pathway that facilitates mitotic slippage." Journal of Cell Biology 215, no. 2 (October 17, 2016): 151–66. http://dx.doi.org/10.1083/jcb.201601083.

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The anaphase-promoting complex/cyclosome (APC/C) ubiquitin ligase is known to target the degradation of cyclin B1, which is crucial for mitotic progression in animal cells. In this study, we show that the ubiquitin ligase CRL2ZYG-11 redundantly targets the degradation of cyclin B1 in Caenorhabditis elegans and human cells. In C. elegans, both CRL2ZYG-11 and APC/C are required for proper progression through meiotic divisions. In human cells, inactivation of CRL2ZYG11A/B has minimal effects on mitotic progression when APC/C is active. However, when APC/C is inactivated or cyclin B1 is overexpressed, CRL2ZYG11A/B-mediated degradation of cyclin B1 is required for normal progression through metaphase. Mitotic cells arrested by the spindle assembly checkpoint, which inactivates APC/C, often exit mitosis in a process termed “mitotic slippage,” which generates tetraploid cells and limits the effectiveness of antimitotic chemotherapy drugs. We show that ZYG11A/B subunit knockdown, or broad cullin–RING ubiquitin ligase inactivation with the small molecule MLN4924, inhibits mitotic slippage in human cells, suggesting the potential for antimitotic combination therapy.

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7

Stevens, F. E., H. Beamish, R. Warrener, and B. Gabrielli. "Histone deacetylase inhibitors induce mitotic slippage." Oncogene 27, no. 10 (September 10, 2007): 1345–54. http://dx.doi.org/10.1038/sj.onc.1210779.

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8

Sloss, O., C. Topham, and S. Taylor. "Mcl-1 dynamics influence mitotic slippage and death in mitosis." European Journal of Cancer 61 (July 2016): S100—S101. http://dx.doi.org/10.1016/s0959-8049(16)61352-7.

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9

Sloss, Olivia, Caroline Topham, Maria Diez, and Stephen Taylor. "Mcl-1 dynamics influence mitotic slippage and death in mitosis." Oncotarget 7, no. 5 (January 12, 2016): 5176–92. http://dx.doi.org/10.18632/oncotarget.6894.

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10

Balachandran, Riju S., and Edward T. Kipreos. "Addressing a weakness of anticancer therapy with mitosis inhibitors: Mitotic slippage." Molecular & Cellular Oncology 4, no. 2 (January 5, 2017): e1277293. http://dx.doi.org/10.1080/23723556.2016.1277293.

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11

Mantel, Charlie, Sara Rhorabough, Ying Guo, Man-Ryul Lee, Myung-Kwan Han, Kye-Seong Kim, and Hal E. Broxmeyer. "Molecular Mechanisms of Spindle Checkpoint-Apoptosis Linkage and Karyotypic Stability in Stem Cells." Blood 110, no. 11 (November 16, 2007): 3361. http://dx.doi.org/10.1182/blood.v110.11.3361.3361.

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Abstract Ex-vivo expansion of human HSC prior to bone marrow transplantation is still an unrealized goal that could greatly extend the usefulness of this mainstay strategy for treating numerous human hematologic diseases. The safety of this process for potential use in humans depends in large part on the maintenance of karyotypic stability of HSC during expansion, a lack of which could contribute to serious, even fatal, complications such as cancer, and could also contribute to engraftment failure. The spindle checkpoint and its linkage to apoptosis initiation is one of the most important cellular processes that helps maintain chromosomal stability in rapidly proliferating cell populations by removing aneuploid and karyotypically abnormal cells via activation of cell death programs. Detailed understanding of the molecular regulation of this vital cell cycle checkpoint is important to maximize safety of in-vitro HSC expansion techniques. It is widely accepted that mammalian cells enter the next G1-phase with 4N DNA after slippage from prolonged drug-induced mitotic block caused by activation of the transient spindle checkpoint that it is from this state that polyploid/aneuploid cells initiate apoptosis. However, definitive biochemical evidence for G1 is scarce or unconvincing; in part because of methods of protein extraction required for immunoblot analysis that cannot take into account the cell cycle heterogeneity of cell cultures. We used single-cell-intracellular-flow-cytometric analysis to define important factors determining cell fate after mitotic slippage. Results from human and mouse embryonic stem cells that reenter polyploid cell cycles are compared to human somatic hematopoietic cells that die after MS. We now report for the first time that phosphorylation status of pRb, p53, CDK1, and cyclin B1 levels are important for cell fate/apoptosis decision in mitotic-slippage cells, which occurs in a unique, intervening, non-G1, tetraploid subphase. Hyperphosphorylated Rb was extremely abundant in mitotic-slippage cells, a cell signaling event usually associated with early G1-S phase transition. P53 was phosphorylated at sites known to be associated with apoptosis regulation. Cyclin A and B1 were undetectable in mitotic slippage cells; yet, CDK1 was phosphorylated at sites typically associated with its activation. Evidence is also presented raising the possibility of cyclin B1-independent CDK1 activity in mitotic-slippage cells. These findings challenge the current models of spindle checkpoint-apoptosis linkages. Our new model could have important implications for methods to maintain karyotypic stability during ex-vivo HSC expansion.

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12

Scott, Stacey J., Xiaodun Li, Sriganesh Jammula, Ginny Devonshire, Catherine Lindon, Rebecca C. Fitzgerald, and Pier Paolo D’Avino. "Evidence that polyploidy in esophageal adenocarcinoma originates from mitotic slippage caused by defective chromosome attachments." Cell Death & Differentiation 28, no. 7 (March 1, 2021): 2179–93. http://dx.doi.org/10.1038/s41418-021-00745-8.

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AbstractPolyploidy is present in many cancer types and is increasingly recognized as an important factor in promoting chromosomal instability, genome evolution, and heterogeneity in cancer cells. However, the mechanisms that trigger polyploidy in cancer cells are largely unknown. In this study, we investigated the origin of polyploidy in esophageal adenocarcinoma (EAC), a highly heterogenous cancer, using a combination of genomics and cell biology approaches in EAC cell lines, organoids, and tumors. We found the EAC cells and organoids present specific mitotic defects consistent with problems in the attachment of chromosomes to the microtubules of the mitotic spindle. Time-lapse analyses confirmed that EAC cells have problems in congressing and aligning their chromosomes, which can ultimately culminate in mitotic slippage and polyploidy. Furthermore, whole-genome sequencing, RNA-seq, and quantitative immunofluorescence analyses revealed alterations in the copy number, expression, and cellular distribution of several proteins known to be involved in the mechanics and regulation of chromosome dynamics during mitosis. Together, these results provide evidence that an imbalance in the amount of proteins implicated in the attachment of chromosomes to spindle microtubules is the molecular mechanism underlying mitotic slippage in EAC. Our findings that the likely origin of polyploidy in EAC is mitotic failure caused by problems in chromosomal attachments not only improves our understanding of cancer evolution and diversification, but may also aid in the classification and treatment of EAC and possibly other highly heterogeneous cancers.

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13

Schuyler, Scott C., and Hsin-Yu Chen. "Using Budding Yeast to Identify Molecules That Block Cancer Cell ‘Mitotic Slippage’ Only in the Presence of Mitotic Poisons." International Journal of Molecular Sciences 22, no. 15 (July 26, 2021): 7985. http://dx.doi.org/10.3390/ijms22157985.

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Research on the budding yeast Saccharomyces cerevisiae has yielded fundamental discoveries on highly conserved biological pathways and yeast remains the best-studied eukaryotic cell in the world. Studies on the mitotic cell cycle and the discovery of cell cycle checkpoints in budding yeast has led to a detailed, although incomplete, understanding of eukaryotic cell cycle progression. In multicellular eukaryotic organisms, uncontrolled aberrant cell division is the defining feature of cancer. Some of the most successful classes of anti-cancer chemotherapeutic agents are mitotic poisons. Mitotic poisons are thought to function by inducing a mitotic spindle checkpoint-dependent cell cycle arrest, via the assembly of the highly conserved mitotic checkpoint complex (MCC), leading to apoptosis. Even in the presence of mitotic poisons, some cancer cells continue cell division via ‘mitotic slippage’, which may correlate with a cancer becoming refractory to mitotic poison chemotherapeutic treatments. In this review, knowledge about budding yeast cell cycle control is explored to suggest novel potential drug targets, namely, specific regions in the highly conserved anaphase-promoting complex/cyclosome (APC/C) subunits Apc1 and/or Apc5, and in a specific N-terminal region in the APC/C co-factor cell division cycle 20 (Cdc20), which may yield molecules which block ‘mitotic slippage’ only in the presence of mitotic poisons.

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14

Orth, James D., Alexander Loewer, Galit Lahav, and Timothy J. Mitchison. "Prolonged mitotic arrest triggers partial activation of apoptosis, resulting in DNA damage and p53 induction." Molecular Biology of the Cell 23, no. 4 (February 15, 2012): 567–76. http://dx.doi.org/10.1091/mbc.e11-09-0781.

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Mitotic arrest induced by antimitotic drugs can cause apoptosis or p53-dependent cell cycle arrest. It can also cause DNA damage, but the relationship between these events has been unclear. Live, single-cell imaging in human cancer cells responding to an antimitotic kinesin-5 inhibitor and additional antimitotic drugs revealed strong induction of p53 after cells slipped from prolonged mitotic arrest into G1. We investigated the cause of this induction. We detected DNA damage late in mitotic arrest and also after slippage. This damage was inhibited by treatment with caspase inhibitors and by stable expression of mutant, noncleavable inhibitor of caspase-activated DNase, which prevents activation of the apoptosis-associated nuclease caspase-activated DNase (CAD). These treatments also inhibited induction of p53 after slippage from prolonged arrest. DNA damage was not due to full apoptosis, since most cytochrome C was still sequestered in mitochondria when damage occurred. We conclude that prolonged mitotic arrest partially activates the apoptotic pathway. This partly activates CAD, causing limited DNA damage and p53 induction after slippage. Increased DNA damage via caspases and CAD may be an important aspect of antimitotic drug action. More speculatively, partial activation of CAD may explain the DNA-damaging effects of diverse cellular stresses that do not immediately trigger apoptosis.

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15

Salmina, Kristine, Agnieszka Bojko, Inna Inashkina, Karolina Staniak, Magdalena Dudkowska, Petar Podlesniy, Felikss Rumnieks, et al. "“Mitotic Slippage” and Extranuclear DNA in Cancer Chemoresistance: A Focus on Telomeres." International Journal of Molecular Sciences 21, no. 8 (April 16, 2020): 2779. http://dx.doi.org/10.3390/ijms21082779.

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Mitotic slippage (MS), the incomplete mitosis that results in a doubled genome in interphase, is a typical response of TP53-mutant tumors resistant to genotoxic therapy. These polyploidized cells display premature senescence and sort the damaged DNA into the cytoplasm. In this study, we explored MS in the MDA-MB-231 cell line treated with doxorubicin (DOX). We found selective release into the cytoplasm of telomere fragments enriched in telomerase reverse transcriptase (hTERT), telomere capping protein TRF2, and DNA double-strand breaks marked by γH2AX, in association with ubiquitin-binding protein SQSTM1/p62. This occurs along with the alternative lengthening of telomeres (ALT) and DNA repair by homologous recombination (HR) in the nuclear promyelocytic leukemia (PML) bodies. The cells in repeated MS cycles activate meiotic genes and display holocentric chromosomes characteristic for inverted meiosis (IM). These giant cells acquire an amoeboid phenotype and finally bud the depolyploidized progeny, restarting the mitotic cycling. We suggest the reversible conversion of the telomerase-driven telomere maintenance into ALT coupled with IM at the sub-telomere breakage sites introduced by meiotic nuclease SPO11. All three MS mechanisms converging at telomeres recapitulate the amoeba-like agamic life-cycle, decreasing the mutagenic load and enabling the recovery of recombined, reduced progeny for return into the mitotic cycle.

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Rossio, Valentina, Elena Galati, Matteo Ferrari, Achille Pellicioli, Takashi Sutani, Katsuhiko Shirahige, Giovanna Lucchini, and Simonetta Piatti. "The RSC chromatin-remodeling complex influences mitotic exit and adaptation to the spindle assembly checkpoint by controlling the Cdc14 phosphatase." Journal of Cell Biology 191, no. 5 (November 22, 2010): 981–97. http://dx.doi.org/10.1083/jcb.201007025.

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Upon prolonged activation of the spindle assembly checkpoint, cells escape from mitosis through a mechanism called adaptation or mitotic slippage, which is thought to underlie the resistance of cancer cells to antimitotic drugs. We show that, in budding yeast, this mechanism depends on known essential and nonessential regulators of mitotic exit, such as the Cdc14 early anaphase release (FEAR) pathway for the release of the Cdc14 phosphatase from the nucleolus in early anaphase. Moreover, the RSC (remodel the structure of chromatin) chromatin-remodeling complex bound to its accessory subunit Rsc2 is involved in this process as a novel component of the FEAR pathway. We show that Rsc2 interacts physically with the polo kinase Cdc5 and is required for timely phosphorylation of the Cdc14 inhibitor Net1, which is important to free Cdc14 in the active form. Our data suggest that fine-tuning regulators of mitotic exit have important functions during mitotic progression in cells treated with microtubule poisons and might be promising targets for cancer treatment.

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Rossio, Valentina, Elena Galati, and Simonetta Piatti. "Adapt or die: how eukaryotic cells respond to prolonged activation of the spindle assembly checkpoint." Biochemical Society Transactions 38, no. 6 (November 24, 2010): 1645–49. http://dx.doi.org/10.1042/bst0381645.

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Many cancer-treating compounds used in chemotherapies, the so-called antimitotics, target the mitotic spindle. Spindle defects in turn trigger activation of the SAC (spindle assembly checkpoint), a surveillance mechanism that transiently arrests cells in mitosis to provide the time for error correction. When the SAC is satisfied, it is silenced. However, after a variable amount of time, cells escape from the mitotic arrest, even if the SAC is not satisfied, through a process called adaptation or mitotic slippage. Adaptation weakens the killing properties of antimitotics, ultimately giving rise to resistant cancer cells. We summarize here the mechanisms underlying this process and propose a strategy to identify the factors involved using budding yeast as a model system. Inhibition of factors involved in SAC adaptation could have important therapeutic applications by potentiating the ability of antimitotics to cause cell death.

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18

Sinha, Debottam, Pascal H. G. Duijf, and Kum Kum Khanna. "Mitotic slippage: an old tale with a new twist." Cell Cycle 18, no. 1 (January 2, 2019): 7–15. http://dx.doi.org/10.1080/15384101.2018.1559557.

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19

Restall, Ian J., Doris A. E. Parolin, Manijeh Daneshmand, Jennifer E. L. Hanson, Manon A. Simard, Megan E. Fitzpatrick, Ritesh Kumar, Sylvie J. Lavictoire, and Ian A. J. Lorimer. "PKCι depletion initiates mitotic slippage-induced senescence in glioblastoma." Cell Cycle 14, no. 18 (September 17, 2015): 2938–48. http://dx.doi.org/10.1080/15384101.2015.1071744.

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20

Jakhar, Rekha, Monique N. H. Luijten, Alex X. F. Wong, Bing Cheng, Ke Guo, Suat P. Neo, Bijin Au, et al. "Autophagy Governs Protumorigenic Effects of Mitotic Slippage–induced Senescence." Molecular Cancer Research 16, no. 11 (July 23, 2018): 1625–40. http://dx.doi.org/10.1158/1541-7786.mcr-18-0024.

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21

Ruggiero, Antonella, Yuki Katou, Katsuhiko Shirahige, Martial Séveno, and Simonetta Piatti. "The Phosphatase PP1 Promotes Mitotic Slippage through Mad3 Dephosphorylation." Current Biology 30, no. 2 (January 2020): 335–43. http://dx.doi.org/10.1016/j.cub.2019.11.054.

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22

Li, Xue, Yue Feng, Meifang Yan, Xiaomeng Tu, Bin Xie, Fangfang Ni, Chunsheng Qu, and Jie-Guang Chen. "Inhibition of Autism-Related Crm1 Disrupts Mitosis and Induces Apoptosis of the Cortical Neural Progenitors." Cerebral Cortex 30, no. 7 (February 1, 2020): 3960–76. http://dx.doi.org/10.1093/cercor/bhaa011.

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Abstract De novo microdeletion of chromosome 2p15–16.1 presents clinically recognizable phenotypes that include mental retardation, autism, and microcephaly. Chromosomal maintenance 1 (CRM1) is a gene commonly missing in patients with 2p15–16.1 microdeletion and one of two genes found in the smallest deletion case. In this study, we investigate the role and mechanism of Crm1 in the developing mouse brain by inhibiting the protein or knocking down the gene in vivo. Inhibition of Crm1 reduces the proliferation and increases p53-dependent apoptosis of the cortical neural progenitors, thereby impeding the growth of embryonic cerebral cortex. Live imaging of mitosis in ex vivo embryonic brain slices reveals that inhibition of CRM1 arrests the cortical progenitors at metaphase. The arrested cells eventually slip into a pseudo-G1 phase without chromosome segregation. The mitotic slippage cells are marked by persistent expression of the spindle assembly checkpoint (SAC), repressing of which rescues the cells from apoptosis. Our study reveals that activating the SAC and inducing the mitotic slippage may lead to apoptosis of the cortical neural progenitors. The resulting cell death may well contribute to microcephaly associated with microdeletion of chromosome 2p15–16.1 involving CRM1.

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Tao, Weikang, Victoria J. South, Ronald E. Diehl, Joseph P. Davide, Laura Sepp-Lorenzino, Mark E. Fraley, Kenneth L. Arrington, and Robert B. Lobell. "An Inhibitor of the Kinesin Spindle Protein Activates the Intrinsic Apoptotic Pathway Independently of p53 and De Novo Protein Synthesis." Molecular and Cellular Biology 27, no. 2 (November 13, 2006): 689–98. http://dx.doi.org/10.1128/mcb.01505-06.

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ABSTRACT The kinesin spindle protein (KSP), a microtubule motor protein, is essential for the formation of bipolar spindles during mitosis. Inhibition of KSP activates the spindle checkpoint and causes apoptosis. It was shown that prolonged inhibition of KSP activates Bax and caspase-3, which requires a competent spindle checkpoint and couples with mitotic slippage. Here we investigated how Bax is activated by KSP inhibition and the roles of Bax and p53 in KSP inhibitor-induced apoptosis. We demonstrate that small interfering RNA-mediated knockdown of Bax greatly attenuates KSP inhibitor-induced apoptosis and that Bax activation is upstream of caspase activation. This indicates that Bax mediates the lethality of KSP inhibitors and that KSP inhibition provokes apoptosis via the intrinsic apoptotic pathway where Bax activation is prior to caspase activation. Although the BH3-only protein Puma is induced after mitotic slippage, suppression of de novo protein synthesis that abrogates Puma induction does not block activation of Bax or caspase-3, indicating that Bax activation is triggered by a posttranslational event. Comparison of KSP inhibitor-induced apoptosis between matched cell lines containing either functional or deficient p53 reveals that inhibition of KSP induces apoptosis independently of p53 and that p53 is dispensable for spindle checkpoint function. Thus, KSP inhibitors should be active in p53-deficient tumors.

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24

Ohashi, Akihiro. "Different cell fates after mitotic slippage: From aneuploidy to polyploidy." Molecular & Cellular Oncology 3, no. 2 (October 6, 2015): e1088503. http://dx.doi.org/10.1080/23723556.2015.1088503.

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Lee, Christine, Kristine J. Fernandez, Sarah Alexandrou, C. Marcelo Sergio, Niantao Deng, Samuel Rogers, Andrew Burgess, and C. Elizabeth Caldon. "Cyclin E2 Promotes Whole Genome Doubling in Breast Cancer." Cancers 12, no. 8 (August 13, 2020): 2268. http://dx.doi.org/10.3390/cancers12082268.

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Genome doubling is an underlying cause of cancer cell aneuploidy and genomic instability, but few drivers have been identified for this process. Due to their physiological roles in the genome reduplication of normal cells, we hypothesised that the oncogenes cyclins E1 and E2 may be drivers of genome doubling in cancer. We show that both cyclin E1 (CCNE1) and cyclin E2 (CCNE2) mRNA are significantly associated with high genome ploidy in breast cancers. By live cell imaging and flow cytometry, we show that cyclin E2 overexpression promotes aberrant mitosis without causing mitotic slippage, and it increases ploidy with negative feedback on the replication licensing protein, Cdt1. We demonstrate that cyclin E2 localises with core preRC (pre-replication complex) proteins (MCM2, MCM7) on the chromatin of cancer cells. Low CCNE2 is associated with improved overall survival in breast cancers, and we demonstrate that low cyclin E2 protects from excess genome rereplication. This occurs regardless of p53 status, consistent with the association of high cyclin E2 with genome doubling in both p53 null/mutant and p53 wildtype cancers. In contrast, while cyclin E1 can localise to the preRC, its downregulation does not prevent rereplication, and overexpression promotes polyploidy via mitotic slippage. Thus, in breast cancer, cyclin E2 has a strong association with genome doubling, and likely contributes to highly proliferative and genomically unstable breast cancers.

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Vainshelbaum, Ninel Miriam, Kristine Salmina, Bogdan I. Gerashchenko, Marija Lazovska, Pawel Zayakin, Mark Steven Cragg, Dace Pjanova, and Jekaterina Erenpreisa. "Role of the Circadian Clock “Death-Loop” in the DNA Damage Response Underpinning Cancer Treatment Resistance." Cells 11, no. 5 (March 3, 2022): 880. http://dx.doi.org/10.3390/cells11050880.

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Here, we review the role of the circadian clock (CC) in the resistance of cancer cells to genotoxic treatments in relation to whole-genome duplication (WGD) and telomere-length regulation. The CC drives the normal cell cycle, tissue differentiation, and reciprocally regulates telomere elongation. However, it is deregulated in embryonic stem cells (ESCs), the early embryo, and cancer. Here, we review the DNA damage response of cancer cells and a similar impact on the cell cycle to that found in ESCs—overcoming G1/S, adapting DNA damage checkpoints, tolerating DNA damage, coupling telomere erosion to accelerated cell senescence, and favouring transition by mitotic slippage into the ploidy cycle (reversible polyploidy). Polyploidy decelerates the CC. We report an intriguing positive correlation between cancer WGD and the deregulation of the CC assessed by bioinformatics on 11 primary cancer datasets (rho = 0.83; p < 0.01). As previously shown, the cancer cells undergoing mitotic slippage cast off telomere fragments with TERT, restore the telomeres by ALT-recombination, and return their depolyploidised offspring to telomerase-dependent regulation. By reversing this polyploidy and the CC “death loop”, the mitotic cycle and Hayflick limit count are thus again renewed. Our review and proposed mechanism support a life-cycle concept of cancer and highlight the perspective of cancer treatment by differentiation.

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Lee, Jinho, Jin Ah Kim, Robert L. Margolis, and Rati Fotedar. "Substrate degradation by the anaphase promoting complex occurs during mitotic slippage." Cell Cycle 9, no. 9 (May 2010): 1792–801. http://dx.doi.org/10.4161/cc.9.9.11519.

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Walen, Kirsten H. "Mitotic Slippage Process Concealed Cancer-Sought Chromosome Instability Mechanism (S-CIN)." Journal of Cancer Therapy 08, no. 06 (2017): 608–23. http://dx.doi.org/10.4236/jct.2017.86052.

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Toda, Kazuhiro, Kayoko Naito, Satoru Mase, Masaru Ueno, Masahiro Uritani, Ayumu Yamamoto, and Takashi Ushimaru. "APC/C-Cdh1-dependent anaphase and telophase progression during mitotic slippage." Cell Division 7, no. 1 (2012): 4. http://dx.doi.org/10.1186/1747-1028-7-4.

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Archetti, Marco. "Polyploidy as an Adaptation against Loss of Heterozygosity in Cancer." International Journal of Molecular Sciences 23, no. 15 (August 1, 2022): 8528. http://dx.doi.org/10.3390/ijms23158528.

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Polyploidy is common in cancer cells and has implications for tumor progression and resistance to therapies, but it is unclear whether it is an adaptation of the tumor or the non-adaptive effect of genomic instability. I discuss the possibility that polyploidy reduces the deleterious effects of loss of heterozygosity, which arises as a consequence of mitotic recombination, and which in diploid cells leads instead to the rapid loss of complementation of recessive deleterious mutations. I use computational predictions of loss of heterozygosity to show that a population of diploid cells dividing by mitosis with recombination can be easily invaded by mutant polyploid cells or cells that divide by endomitosis, which reduces loss of complementation, or by mutant cells that occasionally fuse, which restores heterozygosity. A similar selective advantage of polyploidy has been shown for the evolution of different types of asexual reproduction in nature. This provides an adaptive explanation for cyclical ploidy, mitotic slippage and cell fusion in cancer cells.

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Chen, Liu, Huang, Li, Zhao, Feng, and Zhao. "Heat Stress-Induced Multiple Multipolar Divisions of Human Cancer Cells." Cells 8, no. 8 (August 13, 2019): 888. http://dx.doi.org/10.3390/cells8080888.

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Multipolar divisions of heated cells has long been thought to stem from centrosome aberrations of cells directly caused by heat stress. In this paper, through long-term live-cell imaging, we provide direct cellular evidences to demonstrate that heat stress can promote multiple multipolar divisions of MGC-803 and MCF-7 cells. Our results show that, besides facilitating centrosome aberration, polyploidy induced by heat stress is another mechanism that causes multipolar cell divisions, in which polyploid cancer cells engendered by mitotic slippage, cytokinesis failure, and cell fusion. Furthermore, we also find that the fates of theses polyploid cells depend on their origins, in the sense that the polyploid cells generated by mitotic slippage experience bipolar divisions with a higher rate than multipolar divisions, while those polyploid cells induced by both cytokinesis failure and cell fusion have a higher frequency of multipolar divisions compared with bipolar divisions. This work indicates that heat stress-induced multiple multipolar divisions of cancer cells usually produce aneuploid daughter cells, and might lead to genetically unstable cancer cells and facilitate tumor heterogeneity.

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Zhu, Yanting, Yuan Zhou, and Jue Shi. "Post-slippage multinucleation renders cytotoxic variation in anti-mitotic drugs that target the microtubules or mitotic spindle." Cell Cycle 13, no. 11 (April 2, 2014): 1756–64. http://dx.doi.org/10.4161/cc.28672.

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Riffell, Jenna L., Reiner U. Jänicke, and Michel Roberge. "Caspase-3–Dependent Mitotic Checkpoint Inactivation by the Small-Molecule Inducers of Mitotic Slippage SU6656 and Geraldol." Molecular Cancer Therapeutics 10, no. 5 (March 25, 2011): 839–49. http://dx.doi.org/10.1158/1535-7163.mct-10-0909.

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34

Becker, Sven, Klaus Strebhardt, Ranadip Mandal, and Mourad Sanhaji. "Boosting the apoptotic response of high-grade serous ovarian cancers with CCNE1-amplification to paclitaxel by targeting APC/C and the pro-survival protein MCL-1." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e18065-e18065. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e18065.

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e18065 Background: Ovarian cancer exhibits the highest mortality rate among gynecological malignancies. Antimitotic agents, such as paclitaxel, are frontline drugs for the treatment of ovarian cancer. They inhibit microtubule dynamics and their efficiency relies on a prolonged mitotic arrest and the strong activation of the spindle assembly checkpoint (SAC). Although ovarian cancers respond well to paclitaxel, the clinical efficacy is limited due to an early onset of drug resistance, which may rely on a compromised mitosis exit associated with weakend intrinsic apoptosis. Accordingly, we aimed at overcoming SAC silencing that occurs rapidly during paclitaxel-induced mitotic arrest. Methods: To do this, we used a specific anaphase-promoting complex/ cyclosome (APC/C) inhibitor to prevent a premature mitotic exit upon paclitaxel treatment. Furthermore, we investigated the role of the anti-apoptotic BCL-2 family member MCL-1 in determining the fate of ovarian cancer cells with CCNE1-amplification that are challenged with clinically relevant dose of paclitaxel. Results: Using time-laps microscopy we demonstrated that APC/C and MCL-1 inhibition under paclitaxel prevents mitotic slippage in ovarian cancer cells and restores death in mitosis (DIM). Consistent with this, the combinatorial treatment reduced the survival of ovarian cancer cells in 2D and 3D cell models. Since a therapeutic ceiling has been reached with taxanes, it is of utmost importance to develop alternative strategies to improve the patient´s survival. Conclusions: Our study provides not only elements to understand the causes of taxane resistance in CCNE1-amplified ovarian cancers but also suggests a new combinatorial strategy that may improve paclitaxel efficacy in this highly lethal gynecological disease.

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35

Huang, Shiying, Sekar Karthik, Qi Lin, YuChen Du, Ching C. Lau, Adesina Adekunle, Jack M. F. Su, et al. "EMBR-23. KIF11 DEPENDENCY ON P53 MUTATIONAL STATUS IN MEDULLOBLASTOMA." Neuro-Oncology 23, Supplement_1 (June 1, 2021): i10—i11. http://dx.doi.org/10.1093/neuonc/noab090.041.

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Abstract Introduction KIF11, a mitotic kinesin, is a component responsible for assembly and maintenance of mitotic spindle during mitosis. Tumor cells can upregulate KIF11. Inhibition of KIF11 results monopolar spindle formation, resulting in monoastral mitosis in cells. This activates the spindle assembly checkpoint, cells are arrested and prevented from entering cell cycle, resulting in cell death via apoptosis or necrosis, cell division with aneuploidy or mitotic slippage without division into tetraploid G1 phase. Methods We hypothesized that the effect of KIF11 inhibition on medulloblastoma (MB) is dependent of its p53 mutational status. Results Our findings on Hoechst staining demonstrated a small molecule inhibitor of KIF11 which induced apoptosis in p53-wildtype MB cells at 48h (p<0.0001), was able to trigger mitotic catastrophe (p = 0.0010) in p53-mutant MB cells at 24h and subsequent necrosis (p=0.0039) at 48h. KIF11 inhibitor exerted anti-proliferative effects on five MB cell lines at nanomolar concentration range, independent of its p53 mutational status. Cells treated with KIF11 inhibitor were arrested in G2/M phase. Apoptosis was observed on Annexin V flow cytometry 24h after treatment, followed by necrosis after 48h in p53-wildtype cells. In contrast, treated p53-mutant cells underwent necrosis at 24h. Differences in cell death mechanisms upon KIF11 inhibition was confirmed on immunoblotting by upregulated p53 expression and presence of cleaved-PARP and DNA-damage marker in p53-wildtype cells, indicative of apoptosis. While inhibition of KIF11 and increased p53 expression were observed only after 48h, cleaved-PARP expression was detected as early as 24h in p53-wildtype, suggesting KIF11-independent, cleaved-PARP-mediated cell death at 24h. In contrast, treated p53-mutant cells showed decreased p53 expression and absence of cleaved-PARP and DNA-damage marker after 24h. Conclusions Our results suggest that when mitotic arrest is induced, p53-mutant MB cells undergo mitotic catastrophe and necrosis while p53-wildtype MB cells predominantly undergo apoptosis.

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Vitovcova, Barbora, Veronika Skarkova, Kamil Rudolf, and Emil Rudolf. "Biology of Glioblastoma Multiforme—Exploration of Mitotic Catastrophe as a Potential Treatment Modality." International Journal of Molecular Sciences 21, no. 15 (July 27, 2020): 5324. http://dx.doi.org/10.3390/ijms21155324.

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Glioblastoma multiforme (GBM) represents approximately 60% of all brain tumors in adults. This malignancy shows a high biological and genetic heterogeneity associated with exceptional aggressiveness, leading to a poor survival of patients. This review provides a summary of the basic biology of GBM cells with emphasis on cell cycle and cytoskeletal apparatus of these cells, in particular microtubules. Their involvement in the important oncosuppressive process called mitotic catastrophe will next be discussed along with select examples of microtubule-targeting agents, which are currently explored in this respect such as benzimidazole carbamate compounds. Select microtubule-targeting agents, in particular benzimidazole carbamates, induce G2/M cell cycle arrest and mitotic catastrophe in tumor cells including GBM, resulting in phenotypically variable cell fates such as mitotic death or mitotic slippage with subsequent cell demise or permanent arrest leading to senescence. Their effect is coupled with low toxicity in normal cells and not developed chemoresistance. Given the lack of efficient cytostatics or modern molecular target-specific compounds in the treatment of GBM, drugs inducing mitotic catastrophe might offer a new, efficient alternative to the existing clinical management of this at present incurable malignancy.

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Yamada, Chihiro, Aya Morooka, Seira Miyazaki, Masayoshi Nagai, Satoru Mase, Kenji Iemura, Most Naoshia Tasnin, et al. "TORC1 inactivation promotes APC/C-dependent mitotic slippage in yeast and human cells." iScience 25, no. 2 (February 2022): 103675. http://dx.doi.org/10.1016/j.isci.2021.103675.

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38

Xu, Fengfeng L., Youssef Rbaibi, Kirill Kiselyov, John S. Lazo, Peter Wipf, and William S. Saunders. "Mitotic slippage in non-cancer cells induced by a microtubule disruptor, disorazole C1." BMC Chemical Biology 10, no. 1 (2010): 1. http://dx.doi.org/10.1186/1472-6769-10-1.

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39

Raab, Monika, Andrea Krämer, Stephanie Hehlgans, Mourad Sanhaji, Elisabeth Kurunci-Csacsko, Christina Dötsch, Gesine Bug, et al. "Mitotic arrest and slippage induced by pharmacological inhibition of Polo-like kinase 1." Molecular Oncology 9, no. 1 (August 11, 2014): 140–54. http://dx.doi.org/10.1016/j.molonc.2014.07.020.

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40

Dai, Wei, Qi Wang, Tongyi Liu, Malisetty Swamy, Yuqiang Fang, Suqing Xie, Radma Mahmood, Yang-Ming Yang, Ming Xu, and Chinthalapally V. Rao. "Slippage of Mitotic Arrest and Enhanced Tumor Development in Mice with BubR1 Haploinsufficiency." Cancer Research 64, no. 2 (January 15, 2004): 440–45. http://dx.doi.org/10.1158/0008-5472.can-03-3119.

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41

Yasuhira, Shinji, Masahiko Shibazaki, Masao Nishiya, and Chihaya Maesawa. "Paclitaxel-induced aberrant mitosis and mitotic slippage efficiently lead to proliferative death irrespective of canonical apoptosis and p53." Cell Cycle 15, no. 23 (November 7, 2016): 3268–77. http://dx.doi.org/10.1080/15384101.2016.1242537.

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42

Downes, C. S., C. Z. Bachrati, S. J. Devlin, M. Tommasino, T. J. Cutts, J. V. Watson, I. Rasko, and R. T. Johnson. "Mammalian S-phase checkpoint integrity is dependent on transformation status and purine deoxyribonucleosides." Journal of Cell Science 113, no. 6 (March 15, 2000): 1089–96. http://dx.doi.org/10.1242/jcs.113.6.1089.

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In eukaryotic cells arrested in S-phase, checkpoint controls normally restrain mitosis until after replication. We have identified an array of previously unsuspected factors that modulate this restraint, using transformed hamster cells in which cycle controls are known to be altered in S-phase arrest. Arrested cells accumulate cyclin B, the regulatory partner of the mitotic p34(cdc2) kinase, which is normally not abundant until late G(2) phase; treatment of arrested cells with caffeine produces rapid S-phase condensation. We show here that such S-phase checkpoint slippage, as visualised through caffeine-dependent S-phase condensation, correlates with rodent origin and transformed status, is opposed by reverse transformation, and is favoured by c-src and opposed by wnt1 overexpression. Slippage is also dependent on a prolonged replicative arrest, and is favoured by arrest with hydroxyurea, which inhibits ribonucleotide reductase. This last is a key enzyme in deoxyribonucleotide synthesis, recently identified as a determinant of malignancy. Addition of deoxyribonucleosides shows that rapid S-phase condensation is suppressed by a novel checkpoint mechanism: purine (but not pyrimidine) deoxyribonucleosides, like reverse transformation, suppress cyclin B/p34(cdc2) activation by caffeine, but not cyclin B accumulation. Thus, ribonucleotide reductase has an unexpectedly complex role in mammalian cell cycle regulation: not only is it regulated in response to cycle progression, but its products can also reciprocally influence cell cycle control kinase activation.

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Marxer, M., H. T. Ma, W. Y. Man, and R. Y. C. Poon. "p53 deficiency enhances mitotic arrest and slippage induced by pharmacological inhibition of Aurora kinases." Oncogene 33, no. 27 (August 19, 2013): 3550–60. http://dx.doi.org/10.1038/onc.2013.325.

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Lok, Tsun Ming, Yang Wang, Wendy Kaichun Xu, Siwei Xie, Hoi Tang Ma, and Randy Y. C. Poon. "Mitotic slippage is determined by p31comet and the weakening of the spindle-assembly checkpoint." Oncogene 39, no. 13 (February 6, 2020): 2819–34. http://dx.doi.org/10.1038/s41388-020-1187-6.

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45

Riffell, J. L., and M. Roberge. "731 Chemical induction of mitotic slippage by proteolytic degradation of spindle assembly checkpoint proteins." European Journal of Cancer Supplements 8, no. 5 (June 2010): 184–85. http://dx.doi.org/10.1016/s1359-6349(10)71528-7.

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46

Xiao, J., P. Qiu, X. Lai, P. He, Y. Wu, B. Du, and Y. Tan. "Cyclin-dependent kinase 1 inhibitor RO3306 promotes mitotic slippage in paclitaxel-treated HepG2 cells." Neoplasma 61, no. 01 (2014): 41–47. http://dx.doi.org/10.4149/neo_2014_007.

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47

Schnerch, Dominik, Julia Felthaus, Monika Engelhardt, and Ralph Wäsch. "A Rationale to Enhance the Response to Antimitotic Therapy in Acute Myeloid Leukemia." Blood 120, no. 21 (November 16, 2012): 1332. http://dx.doi.org/10.1182/blood.v120.21.1332.1332.

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Abstract Abstract 1332 Acute myeloid leukemia (AML) is known to respond only moderately to antimitotic therapy while acute lymphoblastic leukemias can be efficiently targeted using spindle-disrupting agents. The underlying molecular cause for this clinical phenomenon is unknown. Recent evidence suggests that response to antimitotic therapy substantially depends on the stability of the critical mitotic regulator cyclin B. The ability to keep cyclin B expression levels stable during a mitotic block is associated with a good response leading to cell death in mitosis. At the metaphase to anaphase transition of an unperturbed cell division, cyclin B is targeted for degradation by the anaphase-promoting complex/cyclosome (APC/C) to trigger chromosome separation. The spindle assembly checkpoint (SAC) is a surveillance mechanism to ensure that APC/C-mediated ubiquitylation is restricted to cells that show proper attachment of all chromosomes to a functional mitotic spindle. In case of spindle disruption or unattached chromosomes, the spindle checkpoint stays active which leads to interference with APC/C-dependent proteolysis of cyclin B blocking cells in prometaphase until every chromosome is attached to the mitotic spindle. We recently developed a cell line-based reporter system which allows monitoring of cyclin B degradation under various conditions (Schnerch et al. Cell Cycle 2012). Here, we identified a pattern of slow degradation of cyclin B which continues through a mitotic block in case of chromosomal misalignment in unperturbed cell cycles. Remarkably, we also found prolonged slow degradation to trigger aberrant exit from mitosis in such cells giving rise to tetraploid cells. Therefore, a reduction in slow degradation appears as a promising rationale to foster a mitotic arrest and enhance cell death in mitosis during antimitotic therapy by preventing such mitotic slippage. We exposed our reporter cells to low concentrations of proteasome inhibitor during a spindle poison induced mitotic block to assess whether proteasome inhibition is capable of modulating slow degradation. Importantly, very low doses of proteasome inhibitor were sufficient to reduced the extent of cyclin B slow degradation during the mitotic block. Moreover, we demonstrate that low doses of proteasome inhibitor render the AML cell line Kasumi-1 responsive to low, non-disruptive concentrations of spindle poison (nocodazole and vincristine) leading to remarkable increases in the G2M-fraction. To the best of our knowledge there is no evidence so far that low doses of proteasome inhibitor exert antimitotic effects by interference with protein degradation during mitosis. Importantly, concentration of bortezomib of 1–2ng/ml (such as found in the serum of patients for up to 72h following administration of 1.3mg/m2 bortezomib subcutaneously) were found to exert synergistic effects with antimitotic therapy. Increases in the percentage of G2M cells by 38% were observed in Kasumi-1 cells for the combination of vincristine and bortezomib. Based on these findings, we currently apply our system to probe combinations of proteasome inhibitor with modern tailored therapies that exert their antimitotic effects by activation of the SAC, such as inhibitors of the motor protein Eg5 or of the mitotic kinases Polo-like kinase 1 (Plk1) or Aurora A and B. Using our cell line-based reporter system, we provide evidence in the in vitro setting that modulating slow degradation during antimitotic therapy by proteasome inhibition is a promising rationale to enhance the efficacy of antimitotic drugs. Drug concentrations used are based on published pharmacokinetics in humans and suggest feasibility of the drug combination in vivo. Our approach of targeted drug combinations may provide highly efficient treatment alternatives for patients that are not eligible for induction treatment. Disclosures: No relevant conflicts of interest to declare.

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Novais, Pedro, Patrícia M. A. Silva, Isabel Amorim, and Hassan Bousbaa. "Second-Generation Antimitotics in Cancer Clinical Trials." Pharmaceutics 13, no. 7 (July 2, 2021): 1011. http://dx.doi.org/10.3390/pharmaceutics13071011.

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Mitosis represents a promising target to block cancer cell proliferation. Classical antimitotics, mainly microtubule-targeting agents (MTAs), such as taxanes and vinca alkaloids, are amongst the most successful anticancer drugs. By disrupting microtubules, they activate the spindle assembly checkpoint (SAC), which induces a prolonged delay in mitosis, expected to induce cell death. However, resistance, toxicity, and slippage limit the MTA’s effectiveness. With the desire to overcome some of the MTA’s limitations, mitotic and SAC components have attracted great interest as promising microtubule-independent targets, leading to the so-called second-generation antimitotics (SGAs). The identification of inhibitors against most of these targets, and the promising outcomes achieved in preclinical assays, has sparked the interest of academia and industry. Many of these inhibitors have entered clinical trials; however, they exhibited limited efficacy as monotherapy, and failed to go beyond phase II trials. Combination therapies are emerging as promising strategies to give a second chance to these SGAs. Here, an updated view of the SGAs that reached clinical trials is here provided, together with future research directions, focusing on inhibitors that target the SAC components.

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Tao, Weikang, Victoria J. South, Yun Zhang, Joseph P. Davide, Linda Farrell, Nancy E. Kohl, Laura Sepp-Lorenzino, and Robert B. Lobell. "Induction of apoptosis by an inhibitor of the mitotic kinesin KSP requires both activation of the spindle assembly checkpoint and mitotic slippage." Cancer Cell 8, no. 1 (July 2005): 49–59. http://dx.doi.org/10.1016/j.ccr.2005.06.003.

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50

Liess, Anna K. L., Alena Kucerova, Kristian Schweimer, Dörte Schlesinger, Olexandr Dybkov, Henning Urlaub, Jörg Mansfeld, and Sonja Lorenz. "Dimerization regulates the human APC/C-associated ubiquitin-conjugating enzyme UBE2S." Science Signaling 13, no. 654 (October 20, 2020): eaba8208. http://dx.doi.org/10.1126/scisignal.aba8208.

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At the heart of protein ubiquitination cascades, ubiquitin-conjugating enzymes (E2s) form reactive ubiquitin-thioester intermediates to enable efficient transfer of ubiquitin to cellular substrates. The precise regulation of E2s is thus crucial for cellular homeostasis, and their deregulation is frequently associated with tumorigenesis. In addition to driving substrate ubiquitination together with ubiquitin ligases (E3s), many E2s can also autoubiquitinate, thereby promoting their own proteasomal turnover. To investigate the mechanisms that balance these disparate activities, we dissected the regulatory dynamics of UBE2S, a human APC/C-associated E2 that ensures the faithful ubiquitination of cell cycle regulators during mitosis. We uncovered a dimeric state of UBE2S that confers autoinhibition by blocking a catalytically critical ubiquitin binding site. Dimerization is stimulated by the lysine-rich carboxyl-terminal extension of UBE2S that is also required for the recruitment of this E2 to the APC/C and is autoubiquitinated as substrate abundance becomes limiting. Consistent with this mechanism, we found that dimerization-deficient UBE2S turned over more rapidly in cells and did not promote mitotic slippage during prolonged drug-induced mitotic arrest. We propose that dimerization attenuates the autoubiquitination-induced turnover of UBE2S when the APC/C is not fully active. More broadly, our data illustrate how the use of mutually exclusive macromolecular interfaces enables modulation of both the activities and the abundance of E2s in cells to facilitate precise ubiquitin signaling.

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