Centromere fragmentation is a common mitotic defect of S and G<sub>2</sub>checkpoint override

Beeharry, Neil; Rattner, J. B.; Caviston, Juliane P.; Yen, Tim J.

doi:10.4161/cc.24740

Cited by 25 publications

(40 citation statements)

References 32 publications

(48 reference statements)

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“…22 We confirmed by immunofluorescence that EGF-1 cells treated with gemcitabine resulted in a reduced mitotic index but that the checkpoint arrest was overridden by Bos-I as judged by an increase in the mitotic index (Fig. 5A).…”

Section: Bosutinib Isomer Is a Potent Sensitizer Of Gemcitabine In Pasupporting

confidence: 61%

“…Second, the mitotic figures of these cells displayed a signature defect that is exhibited by cells forced to enter mitosis with incompletely replicated genomes. 22 Early EM studies showed that cells forced into mitosis with unreplicated genomes (MUGs) exhibited highly fragmented chromosomes that included separation of the centromere/kinetochore complex. 23 Using light and electron microscopy, we previously reported observing similar features for cells forced into mitosis after gemcitabine and UCN-01 treatment.…”

Section: Chemosensitization Occurs Through Off-target Activitiesmentioning

confidence: 99%

“…23 Using light and electron microscopy, we previously reported observing similar features for cells forced into mitosis after gemcitabine and UCN-01 treatment. 22 We therefore compared the mitotic figures of gemcitabine-arrested cells treated with Bos-I and UCN-01. Both treatments caused highly fragmented chromosomes and detachment of centromeres from the bulk of the chromosomes (Fig.…”

Section: Chemosensitization Occurs Through Off-target Activitiesmentioning

confidence: 99%

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Re-purposing clinical kinase inhibitors to enhance chemosensitivity by overriding checkpoints

et al. 2014

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Section: Bosutinib Isomer Is a Potent Sensitizer Of Gemcitabine In Pasupporting

confidence: 61%

Section: Chemosensitization Occurs Through Off-target Activitiesmentioning

confidence: 99%

Section: Chemosensitization Occurs Through Off-target Activitiesmentioning

confidence: 99%

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Re-purposing clinical kinase inhibitors to enhance chemosensitivity by overriding checkpoints

et al. 2014

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“…Previous studies have invariably attributed this feature to checkpoint bypass but have variously described it as disorganized spindle (23), centromere fragmentation (24), and failure of chromosomes with intact centromeres to align along the metaphase plate (14). To clarify, we stained cells for Figure 4.…”

Section: Mitotic Aberrance Is a Consequence Of Deranged Replication Mmentioning

confidence: 99%

CHK1 Inhibition Synergizes with Gemcitabine Initially by Destabilizing the DNA Replication Apparatus

et al. 2015

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Combining cell-cycle checkpoint kinase inhibitors with the DNA-damaging chemotherapeutic agent gemcitabine offers clinical appeal, with a mechanistic rationale based chiefly on abrogation of gemcitabine-induced G 2 -M checkpoint activation. However, evidence supporting this mechanistic rationale from chemosensitization studies has not been consistent. Here we report a systematic definition of how pancreatic cancer cells harboring mutant p53 respond to this combination therapy, by combining mathematical models with large-scale quantitative biologic analyses of single cells and cell populations. Notably, we uncovered a dynamic range of mechanistic effects at different ratios of gemcitabine and CHK1 inhibitors. Remarkably, effective synergy was attained even where cells exhibited an apparently functional G 2 -M surveillance mechanism, as exemplified by a lack of both overt premature CDK1 activation and S-phase mitotic entry. Consistent with these findings, S-G 2 duration was extended in treated cells, leading to a definable set of lineage-dependent catastrophic fates. At synergistic drug concentrations, global replication stress was a distinct indicator of chemosensitization as characterized molecularly by an accumulation of S-phase cells with high levels of hyperphosphorylated RPA-loaded single-stranded DNA. In a fraction of these cells, persistent genomic damage was observed, including chromosomal fragmentation with a loss of centromeric regions that prevented proper kinetochore-microtubule attachment. Together, our results suggested a "foot-in-the-door" mechanism for drug synergy where cells were destroyed not by frank G 2 -M phase abrogation but rather by initiating a cumulative genotoxicity that deregulated DNA synthesis. Cancer Res; 75(17); 3583-95. Ó2015 AACR.

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“…As a consequence, since TOP2 is required to decatenate replicated DNA molecules before the onset of chromatid separation during mitosis, treatment with this type of TOP2 inhibitor (e.g. aclarubicin) induces cell death by mitotic catastrophe due to anaphaseassociated fragmentation of catenated chromatids 6 .…”

Section: Introductionmentioning

confidence: 99%

The dual-acting chemotherapeutic agent Alchemix induces cell death independently of ATM and p53

et al. 2014

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Topoisomerase inhibitors are in common use as chemotherapeutic agents although they can display reduced efficacy in chemotherapy-resistant tumours, which have inactivated DNA damage response genes, such as ATM and TP53. Here, we characterize the cellular response to the dual-acting agent, Alchemix (ALX), which is a modified anthraquinone that functions as a topoisomerase inhibitor as well as an alkylating agent. We show that ALX induces a robust DNA damage response at nano-molar concentrations and this is mediated primarily through ATR-and DNA-PK-but not ATM-dependent pathways, despite DNA double strand breaks being generated after prolonged exposure to the drug. Interestingly, exposure of epithelial tumour cell lines to ALX in vitro resulted in potent activation of the G2/M checkpoint, which after a prolonged arrest was bypassed allowing cells to progress into mitosis where they ultimately died by mitotic catastrophe. We also observed effective killing of lymphoid tumour cell lines in vitro following exposure to ALX, although, in contrast, this tended to occur via activation of a p53-independent apoptotic pathway. Lastly, we validate the effectiveness of ALX as a chemotherapeutic agent in vivo by demonstrating its ability to cause a significant reduction in tumour cell growth, irrespective of TP53 status, using a mouse leukaemia xenograft model.Taken together, these data demonstrate that ALX, through its dual action as an alkylating agent and topoisomerase inhibitor, represents a novel anti-cancer agent that could be potentially used clinically to treat refractory or relapsed tumours, particularly those harbouring mutations in DNA damage response genes.

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Centromere fragmentation is a common mitotic defect of S and G₂checkpoint override

Cited by 25 publications

References 32 publications

Re-purposing clinical kinase inhibitors to enhance chemosensitivity by overriding checkpoints

Re-purposing clinical kinase inhibitors to enhance chemosensitivity by overriding checkpoints

CHK1 Inhibition Synergizes with Gemcitabine Initially by Destabilizing the DNA Replication Apparatus

The dual-acting chemotherapeutic agent Alchemix induces cell death independently of ATM and p53

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Centromere fragmentation is a common mitotic defect of S and G2checkpoint override

Cited by 25 publications

References 32 publications

Re-purposing clinical kinase inhibitors to enhance chemosensitivity by overriding checkpoints

Re-purposing clinical kinase inhibitors to enhance chemosensitivity by overriding checkpoints

CHK1 Inhibition Synergizes with Gemcitabine Initially by Destabilizing the DNA Replication Apparatus

The dual-acting chemotherapeutic agent Alchemix induces cell death independently of ATM and p53

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Centromere fragmentation is a common mitotic defect of S and G₂checkpoint override