ArticleCell cycle (Georgetown, Tex.)2014
Chk1 inhibition in p53-deficient cell lines drives rapid chromosome fragmentation followed by caspase-independent cell death.
Article in Cell cycle (Georgetown, Tex.), 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 37 citations in OpenAlex.
- Development of CDK12 as a Cancer Therapeutic Target and Related Inhibitors.Current cancer drug targets · 2025Review
- The Combination of ATM and Chk1 Inhibitors Induces Synthetic Lethality in Colorectal Cancer Cells.Cancers · 2023Article
- Checkpoint kinase‑1 inhibition and etoposide exhibit a strong synergistic anticancer effect on chronic myeloid leukemia cell line K562 by impairing homologous recombination DNA damage repair.Oncology reports · 2020Article
- The CHK1 inhibitor MU380 significantly increases the sensitivity of human docetaxel-resistant prostate cancer cells to gemcitabine through the induction of mitotic catastrophe.Molecular oncology · 2020Article
- Review
- Combinatorial drug screening of mammary cells with induced mesenchymal transformation to identify drug combinations for triple-negative breast cancer.Oncotarget · 2019Article
- Glucocorticoids and checkpoint tyrosine kinase inhibitors stimulate rat pancreatic beta cell proliferation differentially.PloS one · 2019Article
- Sensory neuronal sensitisation occurs through HMGB-1-RAGE and TRPV1 in high-glucose conditions.Journal of cell science · 2018Article
- Analysis of centrosome and DNA damage response in PLK4 associated Seckel syndrome.European journal of human genetics : EJHG · 2017Article
- MK-8776, a novel Chk1 inhibitor, exhibits an improved radiosensitizing effect compared to UCN-01 by exacerbating radiation-induced aberrant mitosis.Translational oncology · 2017Article
- Alternative Chk1-independent S/M checkpoint in somatic cells that prevents premature mitotic entry.Medical oncology (Northwood, London, England) · 2017Article
- Modification of tumour cell metabolism modulates sensitivity to Chk1 inhibitor-induced DNA damage.Scientific reports · 2017Article
- Inhibition of Chk1 with the small molecule inhibitor V158411 induces DNA damage and cell death in an unperturbed S-phase.Oncotarget · 2016Article
- Chk1 inhibition significantly potentiates activity of nucleoside analogs in TP53-mutated B-lymphoid cells.Oncotarget · 2016Article
- Identification of clinically achievable combination therapies in childhood rhabdomyosarcoma.Cancer chemotherapy and pharmacology · 2016Article
- In Silico Exploration of 1,7-Diazacarbazole Analogs as Checkpoint Kinase 1 Inhibitors by Using 3D QSAR, Molecular Docking Study, and Molecular Dynamics Simulations.Molecules (Basel, Switzerland) · 2016Article
- LY2603618, a selective CHK1 inhibitor, enhances the anti-tumor effect of gemcitabine in xenograft tumor models.Investigational new drugs · 2016Article
- Article
- Progression of chromosomal damage induced by etoposide in G2 phase in a DNA-PKcs-deficient context.Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology · 2015Article
- TAp73 transcriptionally represses BNIP3 expression.Cell cycle (Georgetown, Tex.) · 2015Article
Corrections and comments
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Authors and funding
9 authors at 3 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Activation of Checkpoint kinase 1 (Chk1) following DNA damage mediates cell cycle arrest to prevent cells with damaged DNA from entering mitosis. Here we provide a high-resolution analysis of cells as they undergo S- and G₂-checkpoint bypass in response to Chk1 inhibition with the selective Chk1 inhibitor GNE-783. Within 4-8 h of Chk1 inhibition following gemcitabine induced DNA damage, cells with both sub-4N and 4N DNA content prematurely enter mitosis. Coincident with premature transition into mitosis, levels of DNA damage dramatically increase and chromosomes condense and attempt to align along the metaphase plate. Despite an attempt to congress at the metaphase plate, chromosomes rapidly fragment and lose connection to the spindle microtubules. Gemcitabine mediated DNA damage promotes the formation of Rad51 foci; however, while Chk1 inhibition does not disrupt Rad51 foci that are formed in response to gemcitabine, these foci are lost as cells progress into mitosis. Premature entry into mitosis requires the Aurora, Cdk1/2 and Plk1 kinases and even though caspase-2 and -3 are activated upon mitotic exit, they are not required for cell death. Interestingly, p53, but not p21, deficiency enables checkpoint bypass and chemo-potentiation. Finally, we uncover a differential role for the Wee-1 checkpoint kinase in response to DNA damage, as Wee-1, but not Chk1, plays a more prominent role in the maintenance of S- and G₂-checkpoints in p53 proficient cells.
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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.