ArticleCell cycle (Georgetown, Tex.)2013
Centromere fragmentation is a common mitotic defect of S and G2 checkpoint override.
Article in Cell cycle (Georgetown, Tex.), 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 26 citations in OpenAlex.
- Ploidy shapes gemcitabine response through altered potency and delayed cell death.bioRxiv : the preprint server for biology · 2026Article
- The fluoropyrimidine polymer CF10 synergizes with 5-ethynyl-2'-deoxyuridine by promoting telomere attrition and mitotic catastrophe.NAR molecular medicine · 2026Article
- Potent lung tumor promotion by inhaled MWCNT.Nanotoxicology · 2024Article
- ERCC6L2 mitigates replication stress and promotes centromere stability.Cell reports · 2023Article
- Targeting the DNA Damage Response for Cancer Therapy by Inhibiting the Kinase Wee1.Frontiers in oncology · 2022Review
- Mitochondrial activities play a pivotal role in regulating cell cycle in response to doxorubicin.Cell cycle (Georgetown, Tex.) · 2021Article
- Mitsui-7, heat-treated, and nitrogen-doped multi-walled carbon nanotubes elicit genotoxicity in human lung epithelial cells.Particle and fibre toxicology · 2019Article
- Inhibiting Wee1 and ATR kinases produces tumor-selective synthetic lethality and suppresses metastasis.The Journal of clinical investigation · 2019Article
- Prolonged mitotic arrest induced by Wee1 inhibition sensitizes breast cancer cells to paclitaxel.Oncotarget · 2017Article
- Review
- Replication stress in early S phase generates apparent micronuclei and chromosome rearrangement in fission yeast.Molecular biology of the cell · 2015Article
- Managing Single-Stranded DNA during Replication Stress in Fission Yeast.Biomolecules · 2015Review
- The dual-acting chemotherapeutic agent Alchemix induces cell death independently of ATM and p53.Oncogene · 2015Article
- Pixantrone induces cell death through mitotic perturbations and subsequent aberrant cell divisions.Cancer biology & therapy · 2015Article
- PUL21a-Cyclin A2 interaction is required to protect human cytomegalovirus-infected cells from the deleterious consequences of mitotic entry.PLoS pathogens · 2014Article
- Re-purposing clinical kinase inhibitors to enhance chemosensitivity by overriding checkpoints.Cell cycle (Georgetown, Tex.) · 2014Article
- A synthetic lethal screen identifies the Vitamin D receptor as a novel gemcitabine sensitizer in pancreatic cancer cells.Cell cycle (Georgetown, Tex.) · 2014Article
- The CINs of the centromere.Biochemical Society transactions · 2013Review
- Mitotic checkpoints, MUGs and kinetochores.Cell cycle (Georgetown, Tex.) · 2013Article
- Therapeutic S and G2 checkpoint override causes centromere fragmentation in mitosis.Cell cycle (Georgetown, Tex.) · 2013Article
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4 authors at 2 institutions in 2 countries.
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Abstract
DNA damaging agents, including those used in the clinic, activate cell cycle checkpoints, which blocks entry into mitosis. Given that checkpoint override results in cell death via mitotic catastrophe, inhibitors of the DNA damage checkpoint are actively being pursued as chemosensitization agents. Here we explored the effects of gemcitabine in combination with Chk1 inhibitors in a panel of pancreatic cancer cell lines and found variable abilities to override the S phase checkpoint. In cells that were able to enter mitosis, the chromatin was extensively fragmented, as assessed by metaphase spreads and Comet assay. Notably, electron microscopy and high-resolution light microscopy showed that the kinetochores and centromeres appeared to be detached from the chromatin mass, in a manner reminiscent of mitosis with unreplicated genomes (MUGs). Cell lines that were unable to override the S phase checkpoint were able to override a G2 arrest induced by the alkylator MMS or the topoisomerase II inhibitors doxorubicin or etoposide. Interestingly, checkpoint override from the topoisomerase II inhibitors generated fragmented kinetochores (MUGs) due to unreplicated centromeres. Our studies show that kinetochore and centromere fragmentation is a defining feature of checkpoint override and suggests that loss of cell viability is due in part to acentric genomes. Furthermore, given the greater efficacy of forcing cells into premature mitosis from topoisomerase II-mediated arrest as compared with gemcitabine-mediated arrest, topoisomerase II inhibitors maybe more suitable when used in combination with checkpoint inhibitors.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.