PloS one, 2014-06, Vol.9 (6), p.e98891
2014
Details
- Autor(en) / Beteiligte
- Titel
- A high through-put screen for small molecules modulating MCM2 phosphorylation identifies Ryuvidine as an inducer of the DNA damage response
- Ist Teil von
- PloS one, 2014-06, Vol.9 (6), p.e98891
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2014
- Link zum Volltext
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- DNA replication is an essential process for cell division and as such it is a process that is directly targeted by several anticancer drugs. CDC7 plays an essential role in the activation of replication origins and has recently been proposed as a novel target for drug discovery. The MCM DNA helicase complex (MCM2-7) is a key target of the CDC7 kinase, and MCM phosphorylation status at specific sites is a reliable biomarker of CDC7 cellular activity. In this work we describe a cell-based assay that utilizes the "In Cell Western Technique" (ICW) to identify compounds that affect cellular CDC7 activity. By screening a library of approved drugs and kinase inhibitors we found several compounds that can affect CDC7-dependent phosphorylation of MCM2 in HeLa cells. Among these, Mitoxantrone, a topoisomerase inhibitor, and Ryuvidine, previously described as a CDK4 inhibitor, cause a reduction in phosphorylated MCM2 levels and a sudden blockade of DNA synthesis that is accompanied by an ATM-dependent checkpoint response. This study sheds light on the previously observed cytotoxity of Ryuvidine, strongly suggesting that it is related to its effect of causing DNA damage.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1932-6203eISSN: 1932-6203DOI: 10.1371/journal.pone.0098891Titel-ID: cdi_plos_journals_1532986840
- Format
- –
- Schlagworte
- Antitumor agents, Bioindicators, Biology and life sciences, Biomarkers, Cancer, Cell Cycle Proteins - metabolism, Cell division, Cyclin-dependent kinase 4, Damage detection, Deoxyribonucleic acid, DNA, DNA biosynthesis, DNA damage, DNA Damage - drug effects, DNA helicase, DNA repair, DNA replication, DNA Replication - drug effects, DNA synthesis, Drug approval, Drug Discovery, Drugs, Enzyme Activation - drug effects, Enzyme Inhibitors - chemistry, Enzyme Inhibitors - pharmacology, HeLa Cells, High-Throughput Screening Assays - methods, Humans, Inhibitors, Kinases, Medical screening, Medicine and Health Sciences, Minichromosome Maintenance Complex Component 2 - metabolism, Mitoxantrone, Phosphorylation, Phosphorylation - drug effects, Protein-Serine-Threonine Kinases - metabolism, Replication, Replication origins, Reproducibility of Results, Science, Small Molecule Libraries